Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

New insights of T cells in the pathogenesis of psoriasis

Abstract

Psoriasis is one of the most common immune-mediated chronic, inflammatory skin diseases characterized by hyperproliferative keratinocytes and infiltration of T cells, dendritic cells, macrophages and neutrophils. Although the pathogenesis of psoriasis is not fully understood, there is ample evidence suggesting that the dysregulation of immune cells in the skin, particularly T cells, plays a critical role in psoriasis development. In this review, we mainly focus on the pathogenic T cells and discuss how these T cells are activated and involved in the disease pathogenesis. Newly identified ‘professional’ IL-17-producing dermal γδ T cells and their potential role in psoriasis will also be included. Finally, we will briefly summarize the recent progress on the T cell and its related cytokine-targeted therapy for psoriasis treatment.

Introduction

Psoriasis is a common, chronic inflammatory skin disease, affecting about 2% of the worldwide population.1 Psoriasis vulgaris is the most common type of psoriasis, manifested as dry, red raised plaques with adherent silvery scales. Histologically, psoriasis is characterized by hyperproliferation and aberrant differentiation of keratinocytes, dilated, hyperplastic blood vessels as well as an inflammatory infiltration of leukocytes, predominantly into the dermis.2 Until the late 1970s, psoriasis was originally thought to be a disease primarily of dysfunctional epidermal keratinocytes.3 However, substantial clinical and basic research observations indicate that the cellular innate and adaptive immune responses, especially the activation of T cells, play a critical role in the pathogenesis of psoriasis. The successful treatment of psoriasis patients with cyclosporine A, an immunosuppressive agent that inhibits T-cell proliferation and cytokine production, was the first clinical evidence to suggest a potential role of T cells in psoriasis pathogenesis.4 Other T cell-targeted drugs such as anti-CD4 monoclonal antibody and cytotoxic T lymphocyte-associated antigen 4-immunoglobulin were also observed to have a significant therapeutic efficacy in psoriasis treatment.5,6,7 In addition, an earlier in vitro study showing that activated CD4+ T cells from psoriatic lesions could enhance keratinocyte proliferation via secretion of interferon-γ (IFN-γ)8 and the establishment of psoriasis xenograft animal model in severe combined immunodeficient mouse9,10 further confirm the importance of T cells in psoriasis development. Thus, psoriasis is considered to be an organ-specific T cell-driven inflammatory disease and T cells play a dominant pathogenic role in the initiation and maintenance of psoriasis. In the past few years, many new findings on T cells and their contributions to the disease development have challenged our conventional views regarding psoriasis as a T helper (Th) 1-mediated skin disease and prompted us to reassess T-cell functions in psoriasis. In this review, we will summarize recent progress on T cells as well as some important innate immune cells and their roles in the pathogenesis of psoriasis. Finally, we will briefly discuss some newly developed biological agents targeting T cells and the related cytokines, and their therapeutic efficacy in the treatment of psoriasis patients.

What causes the activation of pathogenic T cells in psoriasis?

As a T cell-mediated autoimmune skin disease, an important question in psoriasis that attracts researchers' interest is to understand how the pathogenic T cells become activated during disease development. The close relationship between streptococcal infection and psoriasis have made antigen(s) from streptococcus the main candidate responsible for activating T cells.11,12 The concept of superantigen was initially proposed based on several research findings where psoriasis patients had a restricted T-cell receptor (TCR) Vβ usage in the peripheral blood and lesions.13,14 Additionally, streptococcal exotoxins could induce expression of a skin-homing receptor, cutaneous lymphocyte-associated antigen, on T cells.15 However, an oligoclonal T-cell expansion found in psoriasis lesions has been reported by several independent groups when analyzing TCR usage on the infiltrated T cells, which provides clear evidence in favor of an antigen-specific T-cell response in the local lesion.16,17 Furthermore, the identification of conserved clonal TCR rearrangement within skin lesions from different patients and continuous presence of the same T-cell clone over a prolonged period of time, even in relapsing disease, suggest that the T cells, which mediate chronic psoriasis, are driven by common antigen(s).18,19 These findings along with the fact that streptococcal M protein shares a high similar structure with type I keratins propose a new theory in psoriasis, named molecular mimicry, or disease mimicry. The concept of molecular mimicry explains how anti-streptococcal T cells can be activated in the skin to target-specific tissue antigen(s) and subsequently causing disease.20,21 Indeed, peripheral blood T cells from psoriatic patients but not healthy controls have been shown to respond to several synthetic peptides corresponding to these shared homologous sequence motifs for the production of IFN-γ.22,23 Further study demonstrated that CD8+ T cells in the peripheral blood from psoriasis patients carrying the HLA–Cw6 allele, which has been reported to have a strong association with psoriasis, had a significant IFN-γ response to the peptide selected from the shared sequence by keratin 17 and M6 protein and the predicted HLA–Cw6 binding.24 Additionally, the majority (>90%) of these responding cells express the skin homing cutaneous lymphocyte-associated antigen determinant.24 Autoantigen candidates Ezrin, Maspin, Peroxiredoxin 2 and Heat Shock Protein 27, all of which have homologies to streptococcal proteins, have been shown to react with the sera from psoriasis patients.25

However, several studies from Fry's group suggested that streptococcal M protein might not be the target for the lesional skin T cells.26,27 In these studies, T-cell lines grown from lesional dermis did not respond by proliferation to recombinant M protein.28 Alternatively, they found that at least half of the streptococcal cell wall-specific Th1 cells in psoriasis lesions were specific for streptococcal peptidoglycan (PG), a major component of the Gram-positive bacterial cell wall.29 In dermal lesions, there were observations of increased numbers of macrophages, containing streptococcal PG, within clusters of dermal T cells or in the dermal papillae.29 It is well known that PG is a strong pro-inflammatory stimulus in chronic inflammation through its interaction with dendritic cells (DCs) and monocytes via pattern recognition receptors including Toll-like receptor 2, nucleotide-binding oligomerization domains 1 and 2 and PG recognition proteins 1–4.30,31 Interestingly, the genes encoding the above PG recognition receptors are all located within linkage sites associated with psoriasis.32 On the basis of these findings, the authors proposed that PG is a major etiological factor in psoriasis and an altered innate response to PG might contribute to the enhanced pathogenic T-cell activation and expansion in the psoriasis lesion.33 However, this schema does not well address the role of CD8+ T-cell function in psoriasis, which has been found to be essential for the development of psoriatic lesions.34 Thus, Valdimarsson et al.35 recently proposed a modified schematic model to explain the potential role of CD4+ and CD8+ T cells in the development of psoriasis lesions and how streptococcal infection triggers and maintains psoriasis. In addition to the streptococcal PG, we also found that streptococcal CpG DNA could enhance the proliferation and activation of peripheral T cells from psoriasis patients upon stimulated with streptococcal antigen, indicating that integral function of streptococcal antigen, particularly streptococcal DNA, in the pathogenesis of psoriasis.36 Thus far, the (auto)antigen(s) responsible for activating psoriatic T cells is still controversial and remains to be determined. Future studies should focus on identifying the autoantigen triggering psoriatic T cells, as it could lead to the use of a vaccine therapy for the treatment of psoriasis.

Is psoriasis a Th1 and/or Th17 cell-mediated inflammatory skin disease?

For over 30 years, T cells were classified as Th1 or Th2 cells by production of defining cytokines, IFN-γ and interleukin (IL)-4, respectively. In psoriatic plaques and peripheral blood of psoriatic patients, there were large numbers of CD4+ Th1 and CD8+ cytotoxic T cells type 1 (Tc1) cells as well as elevated cytokine levels of IFN-γ, tumor-necrosis factor (TNF)-α and IL-12, which well defined psoriasis as a Th1 cell-mediated disease.37,38,39 Since then, it has been widely recognized that the interaction of T cells and DCs creates a ‘type 1’ inflammatory environment by secreting large amounts of Th1 type cytokines, leading to the development of psoriasis.40

Recently, a new population of IL-17-producing CD4+ Th cells, named Th17, has been identified and shown to be involved in the models of inflammatory and autoimmune diseases.41,42,43 It has been well documented that IL-23 functions as a key cytokine for the maintenance and development of both murine and human Th17 cells.44,45,46,47 IL-23 is a heterodimeric cytokine that has unique subunit IL-23p19 combined with IL-12p40, shared with IL-12.48 There is growing evidence to suggest that Th17 cells and their related cytokines such as IL-17A, IL-17F, IL-22, IL-21 and IL-26 play essential roles in a variety of chronic inflammatory diseases, including psoriasis. Th17 cells and their downstream effector molecules, which include IL-17A, IL-17F, IL-22, IL-21 and TNF-α, are found at increased levels in psoriatic skin and circulation.49,50,51,52 Moreover, psoriatic skin lesions also contain high mRNA and protein levels of IL-23 compared with non-lesional and normal skin and IL-23 has been found to be produced mainly by the activated macrophages and DCs.53,54,55 Intradermal injection of IL-23 or IL-21 in mice can stimulate keratinocytes proliferation and cause epidermal hyperplasia (acanthosis), which is one of the most significant features in human psoriasis.51,56 Further studies demonstrated that IL-22, IL-17A as well as CC chemokine receptor (CCR) 6 are all required for IL-23-induced psoriasis-like skin inflammation.57,58,59 In addition, IL-22 was also shown to be critical in another murine psoriasiform model triggered by topical application of Toll-like receptor 7/8 agonist Imiquimod.60 More importantly, these released Th17-related cytokines can further act on keratinocytes and other inflammatory cells infiltrated in the skin, thus amplifying the local inflammation as well as causing keratinocyte hyperproliferation. It has been reported that IL-17A can upregulate keratin 17 expression on keratinocytes, which was regarded as a hallmark of psoriasis.61 Meanwhile, IL-17A plus IL-22 can synergistically enhance keratinocyte expression of antimicrobial peptides, although each cytokine modulates distinct inflammatory and keratinocyte-response pathways that compensatively contribute to the psoriatic phenotype.62,63,64

Collectively, these studies indicate the important role of IL-23/Th17 axis in psoriasis development, which challenges the definition of psoriasis to be a Th1 cell-mediated disease. Th1 and Th17 cells are known as distinct polarized Th cell types, but they are often colocalized in pathological environments, as both Th1 and Th17 cells are increased in the psoriatic lesions and peripheral blood.50,52 To address these questions, Kryczek et al.65 found that IFN-γ is a potent promoter of human IL-17+ T-cell trafficking, induction and function. IFN-γ synergized with IL-17 could enhance human normal keratinocyte to produce human β-defensin 2, suggesting that Th1 and Th17 cells may collaboratively interact with each other and contribute to the autoimmune disease pathogenesis.65 This concept is well supported by another study, in which the authors found that there was accumulation of Th1/Th17 cell-polarizing myeloid DCs in the psoriatic lesions.66 Additionally, intradermal injection of IFN-γ into the non-lesional skin of psoriasis patients could induce significant infiltration of T cells and inflammatory DCs as well as the production of chemokines and cytokines, including IL-23.67

Recently, another distinct population of Th cells, which preferentially express CCR10, CCR6 and CCR4 and produce only IL-22, but not IL-17 or IFN-γ, has been characterized and called IL-22-producing Th cells (Th22).68,69 This unique subset of human skin-homing memory T cells may be involved in epidermal immunity and remodeling and dedicated to the skin homeostasis and pathology.70 It has been reported that there were more Th22 cells along with Th1 and Th17 cells in the circulation of psoriatic patients.52 Res et al.71 also demonstrated that there were more IL-22-producing CD8+ T cells (Tc22) along with Tc17 (IL-17-producing CD8+ T cells) in the psoriatic lesions. They found these Th22 and Tc22 cells might arise from IL-17-producing cells (Th17 and Tc17 cells), suggesting these cells acquire plastic ability in their development. Therefore, psoriasis cannot be simply defined as one subset of Th cells-mediated disease. Instead, all these pathogenic Th cells are implicated in the disease development, which interact with other types of T cells, DCs and neutrophils to create a chronic inflammatory environment for the maintenance of psoriatic plaque.

Innate immune T cells or innate effector cells in psoriasis pathogenesis

In addition to these conventional T cells, more attention has been drawn recently on the innate immune cells, such as gamma delta (γδ) T cells, natural killer (NK) cells and natural killer T (NKT) cells and their potential roles in psoriasis.

Murine skin contains abundant γδ T cells in the epidermis, called dendritic epidermal γδ T cells.72,73 The development and function of dendritic epidermal γδ T cells have been well defined for decades.74,75,76 Recently, three laboratories including ours have identified a novel γδ T-cell subset in the dermis.55,77,78 Unlike dendritic epidermal γδ T cells and conventional αβ T cells, dermal γδ T cells constitutively express IL-23 receptor, CCR6 and transcriptional factor RORγt. More importantly, these cells are demonstrated to be the major IL-17 producer in the skin upon IL-23 stimulation. It has been demonstrated that γδ T cells from other anatomical sites have important pathogenic roles in some infectious and autoimmune diseases through their ability to rapidly produce IL-17 upon IL-23 and IL-1β or danger signal stimulation even in the absence of TCR ligation.79,80,81 Thus, γδ T cells are considered as innate-like cells and can amplify the conventional acquired immune response. Not surprisingly, as ‘professional’ IL-17-producing cells, dermal γδ T cells are also found very critical in the psoriasis pathogenesis.55 In TCR δ-deficient (TCRd−/−) mice, the epidermal hyperplasia and inflammation induced by IL-23 and Imiquimod were significantly decreased. Consistent with our finding, Mabuchi et al.82 also showed IL-23 induced less severe skin pathology in TCRd−/− mice, but they claimed there were specific epidermal CCR6 positive γδ T cells which were responsible in this murine skin inflammation model. The discrepancy between their findings and ours could be explained by the possibility that dermal γδ T cells might migrate into the epidermis during the inflammation. This notion is supported by the finding that this subset of γδ T cells is scarce in epidermis under a steady condition.55 We also found that dermal γδ T cells expanded upon IL-23 stimulation. Importantly, high frequency of γδ T cells was found in the lesions of psoriatic patients, which closely link the murine model system to the clinics. These γδ T cells in the human skin were also capable of producing large amounts of IL-17 upon IL-23 stimulation as the murine counterpart did. Recently, Nestle's group also reported a novel skin homing Vγ9Vδ2 T-cell subset in humans, which expressed cutaneous lymphocyte-associated antigen and other skin homing chemokine receptors. In psoriasis patients, this population was found to be significantly decreased in the peripheral blood, but increased in the lesion.83 Taken together, we assume these γδ T cells present in the skin may become the first line of defense against the invasion of foreign pathogens or the danger signals released upon infection. The released cytokines after γδ T-cell activation can further trigger the downstream immune response, thus causing the chronic inflammation in the local skin. Thus far, the function of dermal γδ T cells, especially in humans, is not fully understood and need to be further investigated in the future.

Additional innate immune cells involved in psoriasis are NK and NKT cells. NKT cells are a heterogenous subset of T cells that share features of both T cells and NK cells. Activated NKT cells can induce psoriasis in xenograft mouse model by using non-lesional psoriatic skin.84,85 Both NK and NKT cells infiltrations have been found significantly increased in psoriatic lesions.86,87 Infiltrating NK cells express CXCR3, CCR5 and CCR6 as well, which are in response to the corresponding chemokines CXCL10, CCL5 or CCL20 secreted by keratinocytes. Additionally, psoriatic NK cells might have increased cytotoxicity through the release of cytotoxic granules such as perforin, which were found upregulated in the psoriatic lesions.87 Recently, NKT cells have been demonstrated to be a potent IL-17 producer, suggesting that these cells may act similarly as dermal γδ T cells in psoriasis pathogenesis.88

In addition to these unconventional T cells, Lin et al.89 reported that mast cells and neutrophils were prominent cells that produced IL-17 in the skin of healthy controls as well as psoriasis patients. In addition, it has been shown that there is a specific IL-23-responsive innate lymphoid population in the intestine, which mediates intestinal immunopathology in inflammatory bowel disease.90 It is possible there might be a similar cell population in psoriatic lesions.

Regulatory T cells (Tregs)

Tregs are a subset of T lymphocytes that suppress not only autoimmune responses but also other aberrant or excessive immune responses to non-self-antigens.91 Although similar proportions of Tregs have been found in normal and psoriatic peripheral blood, both in vitro and in vivo experiments have suggested that Tregs did not function properly in psoriatic plaques. Psoriatic Tregs, in which cells were isolated from lesional psoriatic skin or sorted from peripheral blood of psoriatic patients, are functionally deficient in suppressing effector T-cell responses in either alloantigen-specific or polyclonal TCR stimulation assays.92 Furthermore, in a psoriasis mouse model which was established by knocking out CD18, the primary dysfunction of Tregs has been found to allow subsequent hyperproliferation of pathogenic T cells.93 The possible mechanism by which Tregs exhibit decreased suppression function is partially due to the pro-inflammatory cytokine milieu in the psoriasis lesion, especially high levels of IL-6 secreted from endothelial cells, DCs and Th17 cells, which inhibit Treg activity and enable infiltrated T effector cells escape from the suppression.94,95 Thus, the dysfunctional Treg activity in the blood and psoriatic plaques may eventually result in the reduced restraint and consequent hyperproliferation of psoriatic pathogenic T cells in vivo.92 It has been noticed that CD4+CD25highFoxp3+ Tregs can be converted into inflammation-associate Th17 cells under certain condition. Based on these findings, Bovenschen et al.96 demonstrated that this subset of Tregs from patients with severe psoriasis were more prone to differentiate into IL-17-producing cells compared to healthy controls upon stimulation. Most importantly, they found that there was a specific population of CD4+IL-17A+Foxp3+ cells in the skin lesions, which they assume would probably contribute to the disease development.

T cell-targeted therapy in psoriasis

To date, the Food and Drug Administration has approved various biologic agents for psoriasis therapy include an anti-IL-12/IL-23 common chain p40 antibody,97,98 TNF-α inhibitors99 and T cell-targeted agents. A human antibody against IL-17A or IL-17 receptor is now under phase II clinical trial and has showed a promising therapeutic efficacy.100,101,102 Here, we briefly summarize the recent progress on these biological agents in the treatment of psoriasis.

The pathogenic role of TNF-α in the psoriasis development has made it one of the most important targets for psoriasis therapy. Thus far, there are three Food and Drug Administration-approved anti-TNF-α agents in the market, including etanercept, infliximab and adalimumab and another one, called golimumab, used for the psoriatic arthritis treatment.99 Although all these inhibitors showed the significant therapeutic efficacy, the adverse effects cannot be neglected, especially the increased risk for tuberculosis infection during treatment.103 Another unexpected side effect of TNF-α antagonist treatment from clinical reports is the induction or exacerbation of psoriatic skin lesions.104 This could be caused by the dysregulation of cytokine milieu with the increased production of IFN-α and other pro-inflammatory cytokines, such as IL-1β, IL-6, IL-17, IL-21 and IL-22. Additionally, TNF-α antagonists are also found to enhance Th17 function, but suppress FoxP3+ Tregs in the skin in the murine psoriasis-like model.105 Therefore, the effects of anti-TNF-α agents can be systemic and non-tissue specific, thus caution must be taken when utilizing these agents for therapy.

Recently, the recognition of the importance of IL-23/Th17 axis in psoriasis pathogenesis has prompted the development of new biological agents for psoriasis therapy. Ustekinumab and briakinumab both target IL-12/IL-23 common chain p40 and showed superior efficacy to etanercept in a large clinical study, focusing on the treatment of moderate-to-severe psoriasis.97,98,106 However, serious adverse events have been reported during therapy, which might be due to the broad biological effects of IL-23. In this case, targeting the downstream effector cytokine like IL-17 or IL-22 would be a more logical choice. With great promise, anti-IL-17 antibodies AIN457 (secukinumab) and LY2439821 (ixekizumab) and anti-IL-17 receptor antibody AMG 827 (brodalumab) have shown remarkable therapeutic efficacy in the phase II clinical trials directed towards the treatment of chronic plaque psoriasis.100,101,102 However, their efficacy and safety need to be further assessed in the future.107 Unfortunately, anti-IL-22 antibody (ILV 095) treatment failed in the phase I clinical trial due to lack of efficacy. Although IL-22 plays a critical role in the murine psoriasis development as well as in psoriasis patients, the significance of targeting IL-22 for the disease treatment remains questionable.

Another important therapeutic approach in the treatment of psoriasis is targeting T cells. In addition to anti-CD4 antibodies and T lymphocyte-associated antigen 4-immunoglobulin, here we focus on Efalizumab and Alefacept, which are two recently developed drugs to inhibit T-cell function.

Efalizumab is a humanized, chimeric monoclonal anti-CD11a antibody that binds to the α subunit of leukocyte function-associated antigen (LFA)-1, thereby blocking the interaction of LFA-1 with intercellular adhesion molecule, leading to a disruption of the interaction between DCs and T cells at tissue sites and in lymph nodes.108 It also blocks adhesion molecules between T cells and endothelial cells, thus preventing circulating T cells from entering the skin. However, Efalizumab is no longer marketed due to the required boxed warning by the Food and Drug Administration, which highlights the risk of bacterial sepsis, viral meningitis, invasive fungal disease, progressive multifocal leukoencephalopathy109 and other infection risks after Efalizumab treatment.

Alefacept is a human LFA-3/IgG1 Fc fusion (recombinant) protein that binds to CD2 on memory/effector T cells, selectively blocking the interaction between CD2 on T cells and LFA-3 on antigen-presenting cells, interfering with the function of antigen-presenting cells and T-cell activation.108 It also induces antibody-dependent cellular cytotoxicity in T cells bound to Alefacept and leads to apoptosis of memory-effector CD45RO-positive T cells in the skin. A recent AWARE (Amevive Wisdom Acquired from Real-World Evidence) study supports the safety of alefacept used alone or in combination with other antipsoriatic therapies, in a broad population of chronic plaque psoriasis patients in Canada.110

Another novel T cell-targeted biological drug, called Siplizumab, which is a humanized anti-CD2 monoclonal antibody that interferes with costimulation necessary for T-cell activation and proliferation, has been tested in the clinical trial.111 However, two independent randomized, double-blind, placebo-controlled phase II studies showed that Siplizumab only had modest effects and some clinical activity against inflammatory processes in psoriasis patients, suggesting that targeting CD2+ cells in psoriasis may not yield a therapeutic benefit.

Table 1 is the summary of different subsets of T cells involved in the pathogenesis of psoriasis, including their released pathogenic cytokines and related biological agents for psoriasis therapy.

Table 1 Summary of different subsets of T cells and related cytokines involved in psoriasis pathogenesis

Future directions

The new T-cell subsets, like dermal γδ T cells and Tregs, which are involved in psoriasis pathogenesis, as we mention above, can become the candidates for the future immunotherapy of psoriasis. Current research is focusing on specific subsets of γδ T cells, such as CCR6-positive Vγ9Vδ2, in hopes of expanding our knowledge of the T cells involved in disease development but also in search for more specific targets for future drug therapies. As therapeutic approaches become more specific towards the major players of psoriasis, keen observations of the unexpected, therapeutic side effects will provide greater knowledge pertaining to these newcomers of psoriasis. As more human genomic data from psoriasis patients become available, investigators can begin looking into the genetic underpinnings to the above T-cell interactions and modulations leading to disease development. Perhaps new areas of study such as immunogenomics will give us the tools necessary to clarify elusive problems such as the identity of the autoantigen(s) triggering psoriatic T-cell activation and expansion since these answers could lead to the development of breakthrough immunotherapies.

Conclusions

Over the past few years, there have been great advances on T cells and their roles in the inflammatory and autoimmune diseases that help us understand more deeply the pathogenesis of psoriasis. Instead of the traditional view regarding psoriasis as a Th1 type disease, it is clearer that Th1, Th17, Treg and Th22 cells interplay with each other and all contribute to the disease development. Additionally, newly identified ‘professional’ IL-17-producing dermal γδ T cells also play critical roles in psoriasis pathogenesis. In the schematic model of psoriasis immunopathogenesis depicted in Figure 1, we propose that the pathogens carrying foreign antigens or danger signals first activate the DCs and macrophages to release IL-23, IL-1β and other pro-inflammatory cytokines. These cytokines can activate dermal γδ T cells and other IL-17-producing cells to secrete abundant IL-17 further promoting the conventional acquired immune responses. IL-17, IL-22 and TNF-α can act on keratinocytes and induce keratinocyte hyperproliferation. The activated keratinocytes also release chemokines, such as CCL20 and CXCL1, 3, 8–11, to attract more immune effector cells into the skin. These immune effector cells including neutrophils, mast cells, NK and NKT cells further contribute to the pro-inflammatory environment producing cytokines and chemokines. Thus, this amplified positive feedback loop leads to the development of psoriatic lesions.

Figure 1
figure1

Dysregulated immune responses in psoriasis. Pathogen components or DAMPs activate the DCs and macrophages to produce IL-23, IL-1β and other pro-inflammatory cytokines including IL-6 and TNF-α. These cytokines induce dermal γδ T cells activation and expansion to secrete IL-17, IL-22 and TNF-α, which in turn further promote the conventional CD4+ T cell-mediated (Th1, Th17 and Th22) and CD8+ T cell-mediated (Tc1) acquired immune responses. In addition, skin infiltrating inflammatory cells, such as mast cells, neutrophils, NK cells and NK T cells, also contribute to the disease development via producing cytokines (IL-17), antimicrobial peptides and cytotoxic granules. Additionally, the dysfunctional Tregs lose their suppressive activity and some of them are able to convert to Th17 effector cells, further enhancing the inflammatory reaction in the local skin. The pro-inflamamtory cytokines and chemokines act on keratinocytes and induce keratinocyte hyperproliferation. The activated keratinocytes also produce some chemokines, such as CCL20 and CXCL1, 3, 8–11, to attract more immune effector cells infiltrating into skin, forming the amplified positive feedback loop, leading to the development of psoriatic lesions. DAMP, damage-associated molecular pattern; DC, dendritic cell; NK, natural killer; Th, T helper; TNF, tumor-necrosis factor; Treg, regulatory T cell.

References

  1. 1

    Nestle FO, Kaplan DH, Barker J . Psoriasis. N Engl J Med 2009; 361: 496–509.

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Griffiths CE, Barker JN . Pathogenesis and clinical features of psoriasis. Lancet 2007; 370: 263–271.

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Voorhees JJ . Pathophysiology of psoriasis. Annu Rev Med 1977; 28: 467–473.

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Mueller W, Herrmann B . Cyclosporin A for psoriasis. N Engl J Med 1979; 301: 555.

    CAS  PubMed  Google Scholar 

  5. 5

    Nicolas JF, Chamchick N, Thivolet J, Wijdenes J, Morel P, Revillard JP . CD4 antibody treatment of severe psoriasis. Lancet 1991; 338: 321.

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Prinz J, Braun-Falco O, Meurer M, Daddona P, Reiter C, Rieber P et al. Chimaeric CD4 monoclonal antibody in treatment of generalised pustular psoriasis. Lancet 1991; 338: 320–321.

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang S et al. Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. J Exp Med 2000; 192: 681–694.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Bata-Csorgo Z, Hammerberg C, Voorhees JJ, Cooper KD . Kinetics and regulation of human keratinocyte stem cell growth in short-term primary ex vivo culture. Cooperative growth factors from psoriatic lesional T lymphocytes stimulate proliferation among psoriatic uninvolved, but not normal, stem keratinocytes. J Clin Invest 1995; 95: 317–327.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Wrone-Smith T, Nickoloff BJ . Dermal injection of immunocytes induces psoriasis. J Clin Invest 1996; 98: 1878–1887.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Nickoloff BJ, Wrone-Smith T . Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis. Am J Pathol 1999; 155: 145–158.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Telfer NR, Chalmers RJ, Whale K, Colman G . The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol 1992; 128: 39–42.

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Gudjonsson JE, Thorarinsson AM, Sigurgeirsson B, Kristinsson KG, Valdimarsson H . Streptococcal throat infections and exacerbation of chronic plaque psoriasis: a prospective study. Br J Dermatol 2003; 149: 530–534.

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Lewis HM, Baker BS, Bokth S, Powles AV, Garioch JJ, Valdimarsson H et al. Restricted T-cell receptor V beta gene usage in the skin of patients with guttate and chronic plaque psoriasis. Br J Dermatol 1993; 129: 514–520.

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Leung DY, Travers JB, Giorno R, Norris DA, Skinner R, Aelion J et al. Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis. J Clin Invest 1995; 96: 2106–2112.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Leung DY, Gately M, Trumble A, Ferguson-Darnell B, Schlievert PM, Picker LJ . Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin 12 production. J Exp Med 1995; 181: 747–753.

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Menssen A, Trommler P, Vollmer S, Schendel D, Albert E, Gürtler L et al. Evidence for an antigen-specific cellular immune response in skin lesions of patients with psoriasis vulgaris. J Immunol 1995; 155: 4078–4083.

    CAS  PubMed  Google Scholar 

  17. 17

    Chang JC, Smith LR, Froning KJ, Schwabe BJ, Laxer JA, Caralli LL et al. CD8+ T cells in psoriatic lesions preferentially use T-cell receptor V beta 3 and/or V beta 13.1 genes. Proc Natl Acad Sci USA 1994; 91: 9282–9286.

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Prinz JC, Vollmer S, Boehncke WH, Menssen A, Laisney I, Trommler P . Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris. Eur J Immunol 1999; 29: 3360–3368.

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Vollmer S, Menssen A, Prinz JC . Dominant lesional T cell receptor rearrangements persist in relapsing psoriasis but are absent from nonlesional skin: evidence for a stable antigen-specific pathogenic T cell response in psoriasis vulgaris. J Invest Dermatol 2001; 117: 1296–1301.

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Prinz JC . Disease mimicry—a pathogenetic concept for T cell-mediated autoimmune disorders triggered by molecular mimicry? Autoimmun Rev 2004; 3: 10–15.

    PubMed  Article  Google Scholar 

  21. 21

    Prinz JC . Psoriasis vulgaris—a sterile antibacterial skin reaction mediated by cross-reactive T cells? An immunological view of the pathophysiology of psoriasis. Clin Exp Dermatol 2001; 26: 326–332.

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Sigmundsdottir H, Sigurgeirsson B, Troye-Blomberg M, Good MF, Valdimarsson H, Jonsdottir I . Circulating T cells of patients with active psoriasis respond to streptococcal M-peptides sharing sequences with human epidermal keratins. Scand J Immunol 1997; 45: 688–697.

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Gudmundsdottir AS, Sigmundsdottir H, Sigurgeirsson B, Good MF, Valdimarsson H, Jonsdottir I . Is an epitope on keratin 17 a major target for autoreactive T lymphocytes in psoriasis? Clin Exp Immunol 1999; 117: 580–586.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24

    Johnston A, Gudjonsson JE, Sigmundsdottir H, Love TJ, Valdimarsson H . Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8+ T cells. Clin Exp Immunol 2004; 138: 83–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Besgen P, Trommler P, Vollmer S, Prinz JC . Ezrin, maspin, peroxiredoxin 2, and heat shock protein 27: potential targets of a streptococcal-induced autoimmune response in psoriasis. J Immunol 2010; 184: 5392–5402.

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Brown DW, Baker BS, Ovigne JM, Fischetti VA, Hardman C, Powles AV et al. Non-M protein(s) on the cell wall and membrane of group A streptococci induce(s) IFN-gamma production by dermal CD4+ T cells in psoriasis. Arch Dermatol Res 2001; 293: 165–170.

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Baker BS, Ovigne JM, Fischetti VA, Powles A, Fry L . Selective response of dermal Th-1 cells to 20–50 kDa streptococcal cell-wall proteins in chronic plaque psoriasis. Scand J Immunol 2003; 58: 335–341.

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Baker BS, Brown DW, Fischetti VA, Ovigne JM, Porter W, Powles A et al. Skin T cell proliferative response to M protein and other cell wall and membrane proteins of group A streptococci in chronic plaque psoriasis. Clin Exp Immunol 2001; 124: 516–521.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Baker BS, Laman JD, Powles A, van der Fits L, Voerman JS, Melief MJ et al. Peptidoglycan and peptidoglycan-specific Th1 cells in psoriatic skin lesions. J Pathol 2006; 209: 174–181.

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Wang ZM, Liu C, Dziarski R . Chemokines are the main proinflammatory mediators in human monocytes activated by Staphylococcus aureus, peptidoglycan, and endotoxin. J Biol Chem 2000; 275: 20260–20267.

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Dziarski R . Peptidoglycan recognition proteins (PGRPs). Mol Immunol 2004; 40: 877–886.

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Valdimarsson H . The genetic basis of psoriasis. Clin Dermatol 2007; 25: 563–567.

    PubMed  Article  Google Scholar 

  33. 33

    Baker BS, Powles A, Fry L . Peptidoglycan: a major aetiological factor for psoriasis? Trends Immunol 2006; 27: 545–551.

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Conrad C, Boyman O, Tonel G, Tun-Kyi A, Laggner U, de Fougerolles A et al. Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nat Med 2007; 13: 836–842.

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Valdimarsson H, Thorleifsdottir RH, Sigurdardottir SL, Gudjonsson JE, Johnston A . Psoriasis—as an autoimmune disease caused by molecular mimicry. Trends Immunol 2009; 30: 494–501.

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Cai YH, Lu ZY, Shi RF, Xue F, Chen XY, Pan M et al. Enhanced proliferation and activation of peripheral blood mononuclear cells in patients with psoriasis vulgaris mediated by streptococcal antigen with bacterial DNA. J Invest Dermatol 2009; 129: 2653–2660.

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 1994; 102: 145–149.

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG . The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999; 113: 752–759.

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Friedrich M, Krammig S, Henze M, Docke WD, Sterry W, Asadullah K . Flow cytometric characterization of lesional T cells in psoriasis: intracellular cytokine and surface antigen expression indicates an activated, memory/effector type 1 immunophenotype. Arch Dermatol Res 2000; 292: 519–521.

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Lew W, Bowcock AM, Krueger JG . Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and “Type 1” inflammatory gene expression. Trends Immunol 2004; 25: 295–305.

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Weaver CT, Hatton RD, Mangan PR, Harrington LE . IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 2007; 25: 821–852.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Steinman L . A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nat Med 2007; 13: 139–145.

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Korn T, Bettelli E, Oukka M, Kuchroo VK . IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27: 485–517.

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Kastelein RA, Hunter CA, Cua DJ . Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 2007; 25: 221–242.

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E et al. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nat Immunol 2008; 9: 650–657.

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Boniface K, Blom B, Liu YJ, de Waal Malefyt R . From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited. Immunol Rev 2008; 226: 132–146.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 2009; 10: 314–324.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13: 715–725.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Boniface K, Guignouard E, Pedretti N, Garcia M, Delwail A, Bernard FX et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin Exp Immunol 2007; 150: 407–415.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 2008; 128: 1207–1211.

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Caruso R, Botti E, Sarra M, Esposito M, Stolfi C, Diluvio L et al. Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis. Nat Med 2009; 15: 1013–1015.

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A . Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010; 130: 1373–1383.

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004; 199: 125–130.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Piskin G, Sylva-Steenland RM, Bos JD, Teunissen MB . In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 2006; 176: 1908–1915.

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Cai Y, Shen X, Ding C, Qi C, Li K, Li X et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 2011; 35: 596–610.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 2006; 203: 2577–2587.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007; 445: 648–651.

    CAS  Article  Google Scholar 

  58. 58

    Hedrick MN, Lonsdorf AS, Shirakawa AK, Richard Lee CC, Liao F, Singh SP et al. CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 2009; 119: 2317–2329.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Rizzo HL, Kagami S, Phillips KG, Kurtz SE, Jacques SL, Blauvelt A . IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. J Immunol 2011; 186: 1495–1502.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60

    van Belle AB, de Heusch M, Lemaire MM, Hendrickx E, Warnier G, Renauld JC et al. IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice. J Immunol 2012; 188: 462–469.

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Shi X, Jin L, Dang E, Chang T, Feng Z, Liu Y et al. IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. J Invest Dermatol 2011; 131: 2401–2408.

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006; 203: 2271–2279.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63

    Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007; 8: 950–957.

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suárez-Fariñas M, Cardinale I et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol 2008; 159: 1092–1102.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L et al. Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J Immunol 2008; 181: 4733–4741.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66

    Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, Abello MV, Novitskaya I, Pierson KC et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest Dermatol 2009; 129: 79–88.

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Johnson-Huang LM, Suarez-Farinas M, Pierson KC, Fuentes-Duculan J, Cueto I, Lentini T et al. A single intradermal injection of IFN-gamma induces an inflammatory state in both non-lesional psoriatic and healthy skin. J Invest Dermatol 2012; 132: 1177–1187.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68

    Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H . Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nat Immunol 2009; 10: 864–871.

    CAS  PubMed  Article  Google Scholar 

  69. 69

    Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F . Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 2009; 10: 857–863.

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 2009; 119: 3573–3585.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Res PC, Piskin G, de Boer OJ, van der Loos CM, Teeling P, Bos JD et al. Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis. PLoS ONE 2010; 5: e14108.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72

    Bergstresser PR, Tigelaar RE, Dees JH, Streilein JW . Thy-1 antigen-bearing dendritic cells populate murine epidermis. J Invest Dermatol 1983; 81: 286–288.

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Hayday AC . γδ cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 2000; 18: 975–1026.

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Asarnow DM, Kuziel WA, Bonyhadi M, Tigelaar RE, Tucker PW, Allison JP . Limited diversity of gamma delta antigen receptor genes of Thy-1+ dendritic epidermal cells. Cell 1988; 55: 837–847.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Jameson J, Havran WL . Skin gammadelta T-cell functions in homeostasis and wound healing. Immunol Rev 2007; 215: 114–122.

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Havran WL, Jameson JM . Epidermal T cells and wound healing. J Immunol 2010; 184: 5423–5428.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

    Gray EE, Suzuki K, Cyster JG . Cutting edge: identification of a motile IL-17-producing gammadelta T cell population in the dermis. J Immunol 2011; 186: 6091–6095.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78

    Sumaria N, Roediger B, Ng LG, Qin J, Pinto R, Cavanagh LL et al. Cutaneous immunosurveillance by self-renewing dermal gammadelta T cells. J Exp Med 2011; 208: 505–518.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    O'Brien RL, Roark CL, Born WK . IL-17-producing gammadelta T cells. Eur J Immunol 2009; 39: 662–666.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80

    Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M . Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 2009; 31: 321–330.

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH . Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 2009; 31: 331–341.

    CAS  Article  PubMed  Google Scholar 

  82. 82

    Mabuchi T, Takekoshi T, Hwang ST . Epidermal CCR6+ γδ T cells are major producers of IL-22 and IL-17 in a murine model of psoriasiform dermatitis. J Immunol 2011; 187: 5026–5031.

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Laggner U, Di Meglio P, Perera GK, Hundhausen C, Lacy KE, Ali N et al. Identification of a novel proinflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis. J Immunol 2011; 187: 2783–2793.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84

    Nickoloff BJ, Wrone-Smith T, Bonish B, Porcelli SA . Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes: detection of T cells expressing receptors typically present on natural killer cells, including CD94, CD158, and CD161. Arch Dermatol 1999; 135: 546–552.

    CAS  PubMed  Google Scholar 

  85. 85

    Nickoloff BJ, Bonish B, Huang BB, Porcelli SA . Characterization of a T cell line bearing natural killer receptors and capable of creating psoriasis in a SCID mouse model system. J Dermatol Sci 2000; 24: 212–225.

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Ottaviani C, Nasorri F, Bedini C, de Pita O, Girolomoni G, Cavani A . CD56brightCD16 NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation. Eur J Immunol 2006; 36: 118–128.

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Kastelan M, Prpic Massari L, Gruber F, Zamolo G, Zauhar G, Coklo M et al. Perforin expression is upregulated in the epidermis of psoriatic lesions. Br J Dermatol 2004; 151: 831–836.

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Cosmi L, de Palma R, Santarlasci V, Maggi L, Capone M, Frosali F et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med 2008; 205: 1903–1916.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89

    Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol 2011; 187: 490–500.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90

    Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 2010; 464: 1371–1375.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91

    Wing K, Sakaguchi S . Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 2010; 11: 7–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92

    Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 2005; 174: 164–173.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93

    Wang H, Peters T, Sindrilaru A, Kess D, Oreshkova T, Yu XZ et al. TGF-beta-dependent suppressive function of Tregs requires wild-type levels of CD18 in a mouse model of psoriasis. J Clin Invest 2008; 118: 2629–2639.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94

    Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD . IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol 2009; 183: 3170–3176.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95

    Clark RA . Skin-resident T cells: the ups and downs of on site immunity. J Invest Dermatol 2010; 130: 362–370.

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Bovenschen HJ, van de Kerkhof PC, van Erp PE, Woestenenk R, Joosten I, Koenen HJ . Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol 2011; 131: 1853–1860.

    CAS  PubMed  Article  Google Scholar 

  97. 97

    Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010; 362: 118–128.

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA . Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol 2011; 165: 661–668.

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Kircik LH, del Rosso JQ . Anti-TNF agents for the treatment of psoriasis. J Drugs Dermatol 2009; 8: 546–559.

    PubMed  Google Scholar 

  100. 100

    Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2010; 2: 52ra72.

    Article  CAS  PubMed  Google Scholar 

  101. 101

    Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012; 366: 1190–1199.

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 2012; 366: 1181–1189.

    CAS  PubMed  Article  Google Scholar 

  103. 103

    Bachmann F, Nast A, Sterry W, Philipp S . Safety and efficacy of the tumor necrosis factor antagonists. Semin Cutan Med Surg 2010; 29: 35–47.

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Collamer AN, Battafarano DF . Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: clinical features and possible immunopathogenesis. Semin Arthritis Rheum 2010; 40: 233–240.

    CAS  PubMed  Article  Google Scholar 

  105. 105

    Ma HL, Napierata L, Stedman N, Benoit S, Collins M, Nickerson-Nutter C et al. Tumor necrosis factor alpha blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells. Arthritis Rheum 2010; 62: 430–440.

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Gordon KB, Langley RG, Gottlieb AB, Papp KA, Krueger GG, Strober BE et al. A phase III, randomized, controlled trial of the fully human IL-12/23 mAb briakinumab in moderate-to-severe psoriasis. J Invest Dermatol 2012; 132: 304–314.

    CAS  PubMed  Article  Google Scholar 

  107. 107

    Waisman A . To be 17 again—anti-interleukin-17 treatment for psoriasis. N Engl J Med 2012; 366: 1251–1252.

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Menter A, Griffiths CE . Current and future management of psoriasis. Lancet 2007; 370: 272–284.

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Korman BD, Tyler KL, Korman NJ . Progressive multifocal leukoencephalopathy, efalizumab, and immunosuppression: a cautionary tale for dermatologists. Arch Dermatol 2009; 145: 937–942.

    PubMed  Article  Google Scholar 

  110. 110

    Bissonnette R, Searles G, Landells I, Shear NH, Papp K, Lui H et al. The AWARE study: methodology and baseline characteristics. J Cutan Med Surg 2009; 13 Suppl 3, S113–S121.

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Bissonnette R, Langley RG, Papp K, Matheson R, Toth D, Hultquist M et al. Humanized anti-CD2 monoclonal antibody treatment of plaque psoriasis: efficacy and pharmacodynamic results of two randomized, double-blind, placebo-controlled studies of intravenous and subcutaneous siplizumab. Arch Dermatol Res 2009; 301: 429–442.

    CAS  PubMed  Article  Google Scholar 

  112. 112

    Raychaudhuri SP . Role of IL-17 in psoriasis and psoriatic arthritis. Clin Rev Allergy Immunol 2012

  113. 113

    Nograles KE, Davidovici B, Krueger JG . New insights in the immunologic basis of psoriasis. Semin Cutan Med Surg 2010; 29: 3–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114

    Sa SM, Valdez PA, Wu J, Jung K, Zhong F, Hall L et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J Immunol 2007; 178: 2229–2240.

    CAS  Article  PubMed  Google Scholar 

  115. 115

    Wolk K, Witte E, Wallace E, Docke WD, Kunz S, Asadullah K et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol 2006; 36: 1309–1323.

    CAS  PubMed  Article  Google Scholar 

  116. 116

    Ortega C, Fernandez AS, Carrillo JM, Romero P, Molina IJ, Moreno JC et al. IL-17-producing CD8+ T lymphocytes from psoriasis skin plaques are cytotoxic effector cells that secrete Th17-related cytokines. J Leukoc Biol 2009; 86: 435–443.

    CAS  PubMed  Article  Google Scholar 

  117. 117

    Raychaudhuri SP, Raychaudhuri SK, Genovese MC . IL-17 receptor and its functional significance in psoriatic arthritis. Mol Cell Biochem 2012; 359: 419–429.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the NIH, the National Psoriasis Foundation and the Arthritis National Research Foundation (JY).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jun Yan.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cai, Y., Fleming, C. & Yan, J. New insights of T cells in the pathogenesis of psoriasis. Cell Mol Immunol 9, 302–309 (2012). https://doi.org/10.1038/cmi.2012.15

Download citation

Keywords

  • Psoriasis,TH1/TH17 cells
  • Gammadelta T cells
  • T cell-targeted theraphy

Further reading

Search

Quick links