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γδ-T cells: an unpolished sword in human anti-infection immunity

Abstract

γδ-T cells represent a small population of immune cells, but play an indispensable role in host defenses against exogenous pathogens, immune surveillance of endogenous pathogenesis and even homeostasis of the immune system. Activation and expansion of γδ-T cells are generally observed in diverse human infectious diseases and correlate with their progression and prognosis. γδ-T cells have both ‘innate’ and ‘adaptive’ characteristics in the immune response, and their anti-infection activities are mediated by multiple pathways that are under elaborate regulation by other immune components. In this review, we summarize the current state of the literature and the recent advancements in γδ-T cell-mediated immune responses against common human infectious pathogens. Although further investigation is needed to improve our understanding of the characteristics of different γδ-T cell subpopulations under specific conditions, γδ-T cell-based therapy has great potential for the treatment of infectious diseases.

Introduction

Infectious disease is one of the major threats to human health and causes substantial global morbidity and mortality. Current strategies for controlling infection principally focus on the pathogens themselves, but neglect the importance of the host factors that are involved in the process of disease.1 However, the rapid emergence of drug resistance in infectious pathogens often leads to costly therapy that is largely ineffective. Moreover, the efficiency of the adaptive immune response induced by vaccines might be significantly impaired by the rapid immune evasion of pathogens through their frequent mutations. To this extent, innate immune cells that recognize the conserved structural components of pathogens and raise rapid responses against the dangerous signals evoked by infections have great potential in anti-infection therapy.

Human γδ-T cells are critical components of the innate immune system and play critical roles in the early response to invasive pathogens. γδ-T cells represent only a minor T-cell population in peripheral blood (2%–10% of CD3+ T cells), but constitute the major subset of resident T cells in mucosa and skin.2 This preferential distribution favors their initial in situ anti-infection activities. Compared with the T-cell receptors (TCRs) of conventional αβ-T cells, the TCRs of γδ-T cells are relatively invariant and the exact ligands they recognize are still unknown.3 Nevertheless, it has been confirmed that γδ TCRs can sense the evolutionarily conserved components of exogenous pathogens as unique receptor agonists and initiate a rapid response against them.4,5

The roles of γδ-T cells are multifaceted and correlate with their distribution and differentiation.2 On the one hand, epidermal γδ-T cells play an indispensable role in limiting and eliminating invasive pathogens and recruiting inflammatory cells to infected locations,6,7 while skin γδ-T cells promote tissue repair by producing keratinocyte growth factor.8 On the other hand, some γδ-T cells, especially IL-17-producing γδ-T cells, have been confirmed to be involved in the pathogenesis of transplantation rejection,9 autoimmune diseases,10,11,12,13 inflammatory diseases14,15 and allergy16 in human and animal models. However, the scarcity of peripheral γδ-T cells and the difficulties in monitoring their fate in vivo make it difficult to achieve a comprehensive understanding of the characteristics of human γδ-T cells. Thus, the general application of γδ-T cell-based immune therapy in treating infectious diseases still needs further support from experimental investigations.

In this review, we will focus on the roles of human γδ-T cells in anti-infection immunity. With insights into the underlying mechanisms and regulation of the γδ-T cell-mediated anti-infection immune responses, this review is expected to provide perspective on the development of γδ-T cell-based immune therapy against infectious diseases in the future.

Roles of γδ-T cells in infectious diseases

Subpopulations of human γδ-T cells

Human γδ-T cells can be classified into two main populations according to their TCR expression, which is determined early in the thymus through TCR-mediated selection:17 Vδ1 and Vδ2 γδ-T cells. Vδ1 γδ-T cells are abundant in the skin, epithelia, intestine and uterus; in contrast, Vδ2 γδ-T cells are the majority of peripheral blood γδ-Τ cells.18 Consistent with their different distributions, these two γδ-Τ−cell subpopulations also exhibit distinct migratory patterns and homing capabilities.17

Although it is still controversial whether γδ-Τ cells are capable of antigen-specific memory in the same manner as αβ-T cells, the memory and activation markers CD27 and CD45RA have been found to be expressed on γδ-T cells.19,20 Similarly to αβ-T cells, γδ-T cells can also be classified into four populations based on their expression of CD27 and CD45RA: naive (CD27+CD45RA+), effector memory (CD27CD45RA), central memory (CD27+CD45RA) and terminally differentiated (CD27CD45RA+).21 More important, subpopulations of γδ-T cells identified by the expressions of CD27 and CD45RA exhibit unique functions during mycobacterial infection that correspond to the functions of their αβ-T cell analogues.21 In addition to these two markers, other surface makers are also detected to identify γδ-T cells of different characteristics. Our recent study demonstrated that human CD56+ Vδ2 γδ-T cells have a higher cytolytic capacity against influenza virus-infected cells than CD56 Vδ2 γδ-T cells, suggesting that the expression of CD56 might be a marker for subsets of γδ-T cells that protect against infection.22

Involvement of γδ-T cells in infectious diseases

The dynamic variation in the quality and quantity of human γδ-T cells affects the initiation, progression and prognosis of infectious diseases. Similarly, the nature of the pathogen affects the response of γδ-T cells. The exact roles of γδ-T-cell subpopulations during infections are dependent on their distinct functions and on the specific pathogens. In the following section, we provide an overview of the involvement of γδ-T cells during infection with different pathogens.

Viruses

Although the mechanisms underlying γδ-T cell-mediated immune responses against viruses are still incompletely understood, their protective effects have been confirmed in several acute and chronic viral infections. The activation and cytokine secretions of γδ-T cells are regarded as indicators of early viral infection.23,24

Similarly to the contribution of murine γδ-T cells during recovery after influenza-caused pneumonia,25 the beneficial effects of human Vγ9Vδ2 γδ-T cells against influenza virus infection have also recently been confirmed by our laboratory.22,26,27 Through the direct killing of virus-infected cells and the production of antiviral cytokines, Vγ9Vδ2 γδ-T cells can control infection by different strains of the influenza virus, such as human seasonal H1N1, pandemic H1N1, and the avian H5N1 and H9N2 viruses.22,26,27 Moreover, these antiviral activities can be significantly improved by phosphoantigen stimulation, which confers sufficient protection on humanized mice to prevent lethal influenza virus infection.28 In addition, another group has shown that γδ-T cells can initiate efficient adaptive immunity through processing and presenting influenza virus-derived peptides to CD4+ and CD8+ T cells.29 Moreover, γδ-T cells have been found to promote the establishment of protective adaptive immunity against West Nile virus by inducing the maturation of dendritic cells (DCs).30 However, the protective functions of γδ-T cells can be impaired by some viruses. It has been shown that herpes simplex virus31 and respiratory syncytial virus32 can directly infect local or peripheral γδ-T-cell subsets, respectively, which results in their dysfunction, although a few protective virus-reactive γδ-T cells could still be detected in patients infected with herpes simplex virus.33

The protective roles of γδ-T cells have also been confirmed in some chronic infectious diseases. Vδ2 γδ-T cells, the minor subpopulation of peripheral blood γδ-T cells, have been found to expand on a large scale during human cytomegalovirus (HCMV) infection.34 These HCMV-reactive Vδ2 γδ-T cells have a more potent ‘virus-specific’ cytotoxicity than their Vδ2+ analogues and show increased elimination of pathogens.35 More importantly, this Vδ2 γδ-T cell-mediated ‘HCMV-specific immune response’ can be induced in the fetal immune system during in utero infection, which offers protection in early life.36 Similarly, γδ-T cells also exhibit beneficial roles in controlling HIV infection.24 γδ-T cells in HIV-infected patients have been found to exhibit antiviral potential through their cell-lytic functions37 and cytokine secretions.38 Although the quantity and quality of γδ-T cells have been found to generally decrease with the advancement of HIV infection,39 the suppressed functions of Vγ9Vδ2 γδ-T cells can be enhanced by stimulation with phosphoantigen,39 which might become a novel target of therapeutic strategies.

γδ-T cells also help control the infection caused by Epstein–Barr virus40 and human hepatitis virus C41 in humans. However, the activation of γδ-T cells by hepatitis virus C might induce excessive inflammation and result in severe side effects.41 In addition, activated γδ-T cells can improve αβ-T cell-mediated specific immune responses against Epstein–Barr virus-induced lymphoma42 and contribute to the suppression of polyomavirus-induced tumor growth.43

Bacteria

Human γδ-T cells can recognize multiple conserved pathogen antigens and raise rapid immune responses. Although they have been found to participate in immune responses during many infections, including salmonellosis, brucellosis, legionellosis, tularemia,44 listeriolisis45 and Escherichia coli infections, the importance of human γδ-T cells in anti-bacterial activity is still controversial because the complicated immune responses initiated by the diverse components and products of bacteria make it difficult to identify the independent roles of γδ-T cells. Recently, successful control of both extracellular Gram-positive (Staphylococcus aureus) and Gram-negative (E. coli and Morganella morganii) bacterial infections in severe combined immunodeficiency mice by adoptive transfer of human Vγ9Vδ2 γδ-T cells offers solid evidence of the potent protective functions of γδ-T cells.46 More importantly, some intracellular bacterial pathogens, such as Mycobacterium tuberculosis, can specifically expand and activate Vγ9Vδ2 γδ-T cells by inducing the production of metabolites (e.g., isopentenyl pyrophosphate, IPP) in infected cells, which strongly suggests the importance of γδ-T cells in infection control.47 Consistent with this finding, the suppression of γδ-T cells by chronic tuberculosis infection can result in a disastrous outcome.48

Other infectious pathogens

In addition to their protective functions in viral and bacterial infections, γδ-T cells have been found to be activated and to help control infections caused by Leishmania49 and Toxoplasma gondii,50 although the γδ-T cell-mediated inflammation also causes some unwanted destruction of surrounding tissue.50 Similarly, the protective roles of γδ-T cells in malaria infection have been confirmed in several independent studies.51,52

HOW DO gd-T CELLS SENSE INFECTIOUS PATHOGENS?

Despite their active roles in diverse human infectious diseases, the pathways that are used by γδ-T cells to sense pathogens and initiate rapid responses remain largely unknown. In this section, we will explore some of the principal signals that are critical for γδ-T cell-mediated anti-infection activity.

Host cell-derived signals

It is generally accepted that most factors that sensitize γδ-T cells originate from host cells rather than from pathogens themselves.23 Although the ligands for γδ TCRs are still elusive, some molecules belonging to the phosphoantigen family have been extensively investigated for their application in activating γδ-T cells based on their specific recognition by Vγ9Vδ2 TCRs. These phosphoantigens are usually natural metabolites of isoprenoid biosynthesis in host cells, which include IPP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, dimethylallyl pyrophosphate (DMAPP)53,54 and bromohydrin pyrophosphate.55 These phosphoantigens can be presented by T cells, monocytes and various antigen-presenting cells (APCs), such as DCs and B cells,56,57 through expression of CD1d58,59 and as-yet unknown non-MHC molecules on host cells.60 The clinical applications of phosphoantigens in γδ-T cell-based therapy will be discussed in a later part of this review.

Similarly to αβ-T cells, γδ-T cells also need secondary signals that are provided by costimulatory molecules to achieve expansion and optimal activation.61,62 Many costimulators, such as CD2,63 CD2864,65 and CD137 (4-1BB),66 are expressed in human γδ-T cells and help to promote their activation. On the contrary, when the inhibitory molecule programmed death 1 was expressed in γδ-T cells, it was found to suppress their expansion through interaction with its ligand when the ligand was expressed on infected cells or tumor-related cells (Daniel Oliver, personal communication). In addition to their roles during activation or inhibition of γδ-T cells, costimulators can modify the differentiation of γδ-T cells. For example, the inducible costimulator–inducible costimulator ligand interaction has been found to arm γδ-T cells with some of the properties of follicular T cells and thus assist in antibody production by B cells.67 In addition to the conventional costimulators that are shared with αβ-T cells, several novel molecules can serve as the secondary signals for the activation of γδ-T cells. It has been found that the expression of junctional adhesion molecule-like protein68 and high-mobility group box 169 by γδ-T cells provides positive signals for the activation of γδ-T cells, whereas stimulation with E-cadherin downregulates their functions.70 The natural killer (NK) cell receptor family is another important group of costimulators for regulating the activity of γδ-T cells, and the balance among stimulatory and inhibitory natural killer WW (NK) cell receptor signals might determine the functions of γδ-T cells. For example, NKG2D and NKG2C promote the activation of γδ-T cells, whereas NKG2A transfers inhibitory signals to them.71,72,73

Pathogen-related antigens

Human γδ-T cells also recognize danger signals derived directly from pathogens. Toll-like receptors (TLRs) are the most important pathogen recognition receptors and are capable of recognizing a broad spectrum of pathogen-associated molecule patterns from infectious pathogens. TLRs play critical roles in the antiviral activities of γδ-T cells.74 The expression of TLRs in resting γδ-T cells is usually weak or undetectable but can be quickly upregulated in activated γδ-T cells. It has been found that activated γδ-T cells express nearly all TLRs, although the expression levels of different TLRs are distinct in different subsets.74 For example, both Vδ275 and Vδ176 γδ-T cells can be activated by TLR4 and TLR5 ligands and exhibit increased anti-bacteria responses, whereas the specific expression of TLR3 in Vδ2 γδ-T cells favors their stimulation through this pathway.74 Moreover, pan-γδ-T cells can be activated77 through stimulation of the heterodimers TLR1/2 and TLR2/6 with a mixture of TLR2 ligands, while the production of Th1 cytokines and the cytolytic activity of γδ-T cells can be enhanced by stimulation with double-stranded RNA78 and DNA79 through TLR3 and TLR9, respectively, during viral infections.

In addition to TLRs, γδ TCRs can induce the anti-infection activity of γδ-T cells by recognizing multiple pathogen-derived peptides80,81,82 and unprocessed pathogen-related proteins such as tetanus toxoid,83 herpes simplex virus glycoprotein I,84 mycobacterial purified protein derivatives,85,86 staphylococcal enterotoxin A,87 listeriolysin O88 and some heat shock proteins,85,89 which undoubtedly improves the efficiency of γδ-T cell-mediated immune responses during the very early phases of infections without the need to interact with APCs. Finally, there are still debates regarding whether γδ-T cells also possess antigen specificity similar to αβ-T cells, although rapid recall expansions of clonotypic γδ-T cells have been found in mycobacterial90 and Listeria monocytogenes53 infections. A recent investigation demonstrating receptor selection in peripheral γδ-T cells supported the existence of antigen-specific memory in human γδ-T cells.91 However, care should be taken when identifying ‘antigen-specific γδ-T cells’ before clarifying whether these ‘memory-like responses’ are antigen-restricted or presenting molecule-restricted.92 For example, the CD1d agonist α-GalCer can independently induce interferon (IFN)-γ production by γδ-T cells regardless of the presenting capability of CD1d,93 which does not classically belong as an antigen-specific immune response.

γδ-T cell-mediated anti-infection immunity

After being sensitized by danger signals derived from pathogens or host cells, γδ-T cells execute their anti-infection activities through multiple pathways. Additionally, the γδ-T cell-mediated immune responses are tightly controlled by multiple intrinsic and extrinsic factors, which guarantee the high efficiency of the immune responses and reduce unwanted destruction caused by excessive inflammation.

Direct anti-infection activity mediated by γδ-T cells

Direct killing of infected cells or infectious pathogens is the most prominent mechanism of the γδ-T cell-mediated anti-infection responses. γδ-T cell-mediated cytotoxicity is carried out through dozens of pathways, including Fas–Fas ligand interaction and secretion of perforin, granzyme B27 and granzyme M.94 In contrast to the cytotoxicity of NK cells, the cytotoxicity mediated by Vγ9Vδ2 γδ-T cells22 and Vδ2 γδ-T cells34 against influenza virus- and HCMV-infected cells can be initiated independent of the antibody-dependent cell-mediated cytotoxicity effect. Consistent with this mechanism, the Fc receptor CD16, a key player in antibody-dependent cell-mediated cytotoxicity, has been shown to improve the anti-viral activity of Vδ2 γδ-T cells by inducing them to produce IFN-γ during HCMV infection.95

In addition to their cytotoxic capacities, γδ-T cells are able to secrete dozens of potent soluble pro-inflammatory molecules and directly attack infectious pathogens. Similarly to its role in HCMV infection, IFN-γ secreted from Vγ9Vδ2 γδ-T cells inhibits influenza virus propagation.26 In addition, IL-17 and tumor-necrosis factor-α secreted by various γδ-T cell populations contribute to the control and elimination of several types of bacteria45,96 and Plasmodium falciparum.51 Recently, IL-22 has been suggested as a potent anti-infection cytokine in the γδ-T cell-mediated anti-infection immune response by some reports.97,98

Indirect anti-infection activity mediated by γδ-T cells

Initiating local immune responses

Local responses aroused during the early phase of infection are crucial for limiting the spread of pathogens. Both resident and circulating γδ-T cells accumulate quickly around invasive pathogens and induce efficient anti-infection responses through collaboration with neighboring immune cells.99 γδ-T cells enhance the anti-infection capabilities of resident macrophages and NK cells,100,101 promote the maturation of DCs6,102 and improve the invasion resistance of epithelial cells.103,104 Importantly, the dynamic interaction between γδ-T cells and their neighbors induces TCR selection of γδ-T cells in situ, leading to more precise responses against specific pathogens.101,103 Similarly to other sentinel cells, γδ-T cells also secrete chemokines such as CCL2, CCL3 and CCL4 to recruit pro-inflammatory neutrophils to accelerate the elimination of pathogens and the repair of damaged tissues.26

APC function

In addition to their direct anti-infection activities, human γδ-T cells act as professional APCs and take up, process and present pathogen-related antigens from both free viral particles29 and infected cells57,105 to other effector immune cells.106,107 These γδ-T APCs express approximately similar levels of HLA-DR and CD80/CD86 compared to traditional APCs29 and induce NK cell activation,108,109 antigen-specific αβ-T-cell responses29,107 and even antibody production.67 Although the physiological roles of γδ-T APCs still need to be illuminated by more in vivo studies, recent investigations of murine γδ-T cells have confirmed the general existence of γδ-T APCs.110

Modifying adaptive immunity

Although generally regarded as a component of the innate immune system based on their invariant TCRs and rapid responses to danger signals, γδ-T cells are now accepted as a crucial player in the adaptive immune system as well.111 The contribution of γδ-T cells to adaptive immunity goes beyond their APC function mentioned above. For example, γδ-T cells are capable of inducing the maturation of DCs,67 facilitating the development of αβ-T cells,13,112 killing regulatory T cells (Tregs)113,114 and migrating into the secondary lymphoid tissues and acting as follicular B helper T cells to promote antibody production.115,116 Moreover, γδ-T cells can compete with αβ-T cells for growth factors such as IL-15 and thus modify the adaptive immune response.117

Treg function

γδ-T cells have also been found to exhibit several ‘regulatory characteristics’ in both humans and mice.118,119 Similarly to conventional CD4+ Tregs, a regulatory Vδ1 γδ-T cell subset identified by the expression of CD27 and CD25 in the peripheral blood of systemic lupus erythematosus patients has been found to correlate with the progression and remission of the disease.120 Moreover, IPP-induced synovial fluid Vγ9Vδ2 γδ-T-cell expansion has been found to ameliorate arthritis.121 However, the contribution of these regulatory γδ-T cells to anti-infection responses is still unclear.

Regulation of γδ-T-mediated anti-infection responses

The immune system is equipped with an elaborate regulatory network, which guarantees its efficiency while avoiding the unnecessary destruction caused by immune responses. In the battle against infectious pathogens, the activity of γδ-T cells is also regulated by other molecules that act through multiple pathways. It has been confirmed that both murine122 and human123 CD4+ Tregs can directly suppress the expansion and cytokine production of mucosal γδ-T cells, whereas effector CD4+ T cells help maintain IL-17 production in γδ-T cells in naive animals.124 These dynamic interactions exist not only between adaptive immunity and innate immunity, but also within the innate immune system itself. For example, NK cells can exhibit inhibitory effects on the activation and cytotoxicity of γδ-T cells and protect pregnant women from preeclampsia.125

In addition to cellular regulation, the development, proliferation and activation of γδ-T cells in anti-infection immune responses are also controlled by multiple soluble molecules, in particular cytokines. Similarly to NK cells, both IL-7 and IL-15 are indispensable during the development and homeostasis of γδ-T cells,126 while IL-15,127 accompanied by IL-17 and IL-22, has also been found to contribute to the activation and expansion of γδ-T cells during M. tuberculosis53 infection. A similar effect that is mediated by IL-23 has been found in Listeria monocytogenes128 infection as well. In addition, IL-7,129 IL-21130 and the caspase-1-processed IL-1 family cytokines IL-1β and IL-18131 increase the anti-infection ability of γδ-T cells by promoting expansion and cytokine production. Moreover, IFN-γ has been found to contribute to the antagonizing effects of γδ-T cells against regulation that is mediated by Tregs.132 In contrast, type I IFN has been found to constrain IL-17A production by γδ-T cells against Francisella tularensis subspecies novicida,133 while administration of either transforming growth factor-β134 or IL-10135 alone inhibits IFN-γ production by γδ-T cells in response to mycobacterial infection. The administration of transforming growth factor-β accompanied by anti-γδ TCR can even induce human and murine γδ-T cells into a regulatory status, thus dampening their anti-infection effects.119,120

Chemokines are another important group of soluble factors that determine the outcome of γδ-T cell-mediated anti-infection immune responses. It has been found that RANTES, MIP1α/β and CXCL9/10/11 secreted from infected cells guide the migration of CCR526- and CXCR3136- expressed IPP-activated Vγ9Vδ2 γδ-T cells to influenza-infected sites and facilitate the elimination of pathogens.

Potential of γδ-T cell-based therapy in infectious diseases

Obstacles to the application of γδ-T cell-based therapy

Current investigations on human γδ-T cells offer a promising future for infectious disease therapeutic strategies, although many questions that need to be answered remain before general application in the clinic will be possible. One major obstacle to γδ-T cell-based therapy is the scarcity of γδ-T cells in peripheral blood. Although phosphoantigens have been globally applied in the expansion of Vγ9Vδ2 γδ-T cells, the in vivo effects of these drugs need to be thoroughly investigated. Another impediment to studying the efficacy of phosphoantigen activation and expansion of Vγ9Vδ2 γδ-T cells is the lack of an analogue in murine systems, which can be overcome by the development of a humanized mouse model.28,137 Similarly, reliable animal models need to be established for evaluating the characteristics and clinical potential of human resident γδ-T cells in mucosa and skin.

Current strategies for activating or expanding γδ-T cells

The approach of using phosphoantigens plus IL-2 has been the most potent and widely accepted protocol for activation and expansion of Vγ9Vδ2 γδ-T cells both in vitro and in vivo.138 For adoptive transfer therapy, a single dose as large as 109 ex vivo expanded Vγ9Vδ2 γδ-T cells has been confirmed to be safe by several independent investigations.139,140,141 Encouragingly, these infused Vγ9Vδ2 γδ-T cells exhibited satisfactory clinical benefit in an anti-tumor trial.142 For in vivo applications, a single dose of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate plus 5 days of IL-2 treatment induced an 80-fold expansion of macaque peripheral blood Vγ9Vδ2 γδ-T cells without detectable side effects.143 More excitingly, the administration of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and IL-2 was confirmed to significantly induce prolonged accumulation of Vγ9Vδ2 γδ-T cells in the lungs of cynomolgus monkeys and ameliorate lung lesions caused by Yersinia pestis infection.144 Presently, bisphosphonates such as Pamidronate and Zoledronate145 are ‘old’ drugs that are routinely applied in treating osteoporosis or Paget's disease and have shown potential benefits in human tumor therapies146,147,148 and for treating influenza infection in humanized mice.28

In addition to phosphoantigens, stimulation that targets TLRs, natural killer (NK) cell receptors or CD3 have also been applied in the activation and expansion of pan-γδ-T cells in vitro.149 In line with these efforts, significant outcomes have been claimed for the usage of anti-γδ TCR antibody accompanied by cytokines in expanding human γδ-T cells,150 which improved the treatment of tumors in a mouse model151 and helped ameliorate autoimmune diseases.120 Nevertheless, the efficacies of these distinct protocols need to be evaluated and compared under standard conditions to achieve the optimal therapeutic effect. Moreover, the associated changes in the phenotypes of these accumulated γδ-T cells need to be clarified before their clinical application.

Prospective and potential limitations

The application of γδ-T cell-based therapy against infectious diseases has a bright future. One of its most prominent advantages comes from the recognition of danger signals rather than of pathogens themselves, which can engage in immune evasion through frequent mutation of epitopes.23 Another advantage of γδ-T cell-based therapy relies on their ability to traffic to local sites of infection.143,152 Moreover, the APC function of γδ-T cells further favors their application in inducing antigen-specific immune responses to efficiently eliminate pathogens.153 Finally, over 40 years of bisphosphonate usage in the clinic offers abundant references for their use in expanding and activating γδ-T cells in vivo, although attention must still be paid to the mild or moderate acute responses evoked by their injection.154,155

The major concern with using γδ-T cell-based anti-infection therapy comes from its pro-inflammatory characteristics. These potential risks might be induced by overdoses or bystander effects and result in γδ-T cell-triggered autoimmune diseases13 or general inflammatory diseases.156 It has been shown that one auto-aggressive γδ-T-cell subset recognizing aminoacyl-tRNA synthetases that are shared by bacteria and humans can be detected in some myositis patients and might contribute to the pathogenesis of their disease.157 Thus, a thorough understanding of the migration, differentiation and transformation of activated γδ-T cells under physiological and pathological conditions158 should be achieved before their clinical application.

Summary

In summary, γδ-T cells play distinct roles in human infectious diseases corresponding to their distribution and subpopulations. The anti-infection activities of γδ-T cells can be initiated by signals from hosts and pathogens and carried out by direct cytotoxicity against infected cells or through cytokine production or by indirect pathways involving multiple immune system components. As a bridge between innate immunity and adaptive immunity, γδ-T cells exhibit diverse advantages in anti-infection responses. Although the potential of γδ-T cells for treating human diseases has been significantly improved with the application of bisphosphonates and the advancement of our understanding of their multifaceted characteristics, the clinical usage of γδ-T cell-based therapies requires more in vivo evidence from further investigations into their roles under physiological and pathological conditions.

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Acknowledgements

This work was supported in part by the Area of Excellence program on influenza, which is supported by the University Grants Committee of the Hong Kong SAR, China (Project No. AoE/M-12/06), the General Research Fund and the Research Grants Council of Hong Kong (HKU 777108M, HKU777407, HKU768108, HKU781211).

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Correspondence to Wenwei Tu.

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Zheng, J., Liu, Y., Lau, YL. et al. γδ-T cells: an unpolished sword in human anti-infection immunity. Cell Mol Immunol 10, 50–57 (2013). https://doi.org/10.1038/cmi.2012.43

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Keywords

  • γδ-T cells
  • infection
  • immunity
  • human

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