Sathaliyawala, T. et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38, 187–197 (2013).
Park, C. O. & Kupper, T. S. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat. Med. 21, 688–697 (2015).
Clark, R. A. Resident memory T cells in human health and disease. Sci. Transl Med. 7, 269rv261 (2015).
Pasparakis, M., Haase, I. & Nestle, F. O. Mechanisms regulating skin immunity and inflammation. Nat. Rev. Immunol. 14, 289–301 (2014).
Kupper, T. S. & Fuhlbrigge, R. C. Immune surveillance in the skin: mechanisms and clinical consequences. Nat. Rev. Immunol. 4, 211–222 (2004).
Elias, P. M. The skin barrier as an innate immune element. Semin. Immunopathol. 29, 3–14 (2007).
Burgeson, R. E. & Christiano, A. M. The dermal-epidermal junction. Curr. Opin. Cell Biol. 9, 651–658 (1997).
Robert, C. & Kupper, T. S. Inflammatory skin diseases, T cells, and immune surveillance. N. Engl. J. Med. 341, 1817–1828 (1999).
Kupper, T. S. The activated keratinocyte: a model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses. J. Invest. Dermatol. 94, 146S–150S (1990).
Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).
Kashem, S. W., Haniffa, M. & Kaplan, D. H. Antigen-presenting cells in the skin. Annu. Rev. Immunol. 35, 469–499 (2017).
Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002).
Clark, R. A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006).
Mueller, S. N., Gebhardt, T., Carbone, F. R. & Heath, W. R. Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 31, 137–161 (2013).
Watanabe, R. et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci. Transl Med. 7, 279ra239 (2015).
Gaide, O. et al. Common clonal origin of central and resident memory T cells following skin immunization. Nat. Med. 21, 647–653 (2015).
Jiang, X. et al. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature 483, 227–231 (2012).
Ahmed, R., Bevan, M. J., Reiner, S. L. & Fearon, D. T. The precursors of memory: models and controversies. Nat. Rev. Immunol. 9, 662–668 (2009).
Chang, J. T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).
Youngblood, B. et al. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552, 404–409 (2017).
Akondy, R. S. et al. Origin and differentiation of human memory CD8 T cells after vaccination. Nature 552, 362–367 (2017).
Carbone, F. R. Tissue-resident memory T cells and fixed immune surveillance in nonlymphoid organs. J. Immunol. 195, 17–22 (2015).
Mackay, C. R. et al. Tissue-specific migration pathways by phenotypically distinct subpopulations of memory T cells. Eur. J. Immunol. 22, 887–895 (1992).
Mackay, C. R., Andrew, D. P., Briskin, M., Ringler, D. J. & Butcher, E. C. Phenotype, and migration properties of three major subsets of tissue homing T cells in sheep. Eur. J. Immunol. 26, 2433–2439 (1996).
Masopust, D., Vezys, V., Marzo, A. L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).
Liu, L., Fuhlbrigge, R. C., Karibian, K., Tian, T. & Kupper, T. S. Dynamic programming of CD8+ T cell trafficking after live viral immunization. Immunity 25, 511–520 (2006).
Mora, J. R., Iwata, M. & von Andrian, U. H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat. Rev. Immunol. 8, 685–698 (2008).
Sigmundsdottir, H. & Butcher, E. C. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat. Immunol. 9, 981–987 (2008).
Sigmundsdottir, H. et al. DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8, 285–293 (2007).
McCully, M. L. et al. Epidermis instructs skin homing receptor expression in human T cells. Blood 120, 4591–4598 (2012).
Yamanaka, K. et al. Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. J. Allergy Clin. Immunol. 121, 148–157 (2008).
Mackay, L. K. et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).
Bergsbaken, T. & Bevan, M. J. Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8+ T cells responding to infection. Nat. Immunol. 16, 406–414 (2015).
Harris, T. H. et al. Generalized Levy walks and the role of chemokines in migration of effector CD8+ T cells. Nature 486, 545–548 (2012).
Nakanishi, Y., Lu, B., Gerard, C. & Iwasaki, A. CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T cell help. Nature 462, 510–513 (2009).
Hickman, H. D. et al. CXCR3 chemokine receptor enables local CD8+ T cell migration for the destruction of virus-infected cells. Immunity 42, 524–537 (2015).
Laidlaw, B. J. et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41, 633–645 (2014).
Liu, L. et al. Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity. Nat. Med. 16, 224–227 (2010).
Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).
Mackay, L. K. et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).
Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).
Campbell, J. J., Clark, R. A., Watanabe, R. & Kupper, T. S. Sezary syndrome and mycosis fungoides arise from distinct T cell subsets: a biologic rationale for their distinct clinical behaviors. Blood 116, 767–771 (2010).
Campbell, J. J. et al. CCR7 expression and memory T cell diversity in humans. J. Immunol. 166, 877–884 (2001).
Gehad, A. et al. A primary role for human central memory cells in tissue immunosurveillance. Blood Adv. 2, 292–298 (2018).
Park, S. L. et al. Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses. Nat. Immunol. 19, 183–191 (2018).
Beura, L. K. et al. Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat. Immunol. 19, 173–182 (2018).
Clark, R. A. et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Transl Med. 4, 117ra117 (2012).
Bromley, S. K., Yan, S., Tomura, M., Kanagawa, O. & Luster, A. D. Recirculating memory T cells are a unique subset of CD4+ T cells with a distinct phenotype and migratory pattern. J. Immunol. 190, 970–976 (2013).
Hogan, R. J. et al. Protection from respiratory virus infections can be mediated by antigen-specific CD4+ T cells that persist in the lungs. J. Exp. Med. 193, 981–986 (2001).
Reinhardt, R. L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M. K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).
Marshall, D. R. et al. Measuring the diaspora for virus-specific CD8+ T cells. Proc. Natl Acad. Sci. USA 98, 6313–6318 (2001).
Teraki, Y. & Shiohara, T. IFN-gamma-producing effector CD8+ T cells and IL-10-producing regulatory CD4+ T cells in fixed drug eruption. J. Allergy Clin. Immunol. 112, 609–615 (2003).
Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. J. Exp. Med. 199, 731–736 (2004).
Clark, R. A. & Kupper, T. S. IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood 109, 194–202 (2007).
Thome, J. J. & Farber, D. L. Emerging concepts in tissue-resident T cells: lessons from humans. Trends Immunol. 36, 428–435 (2015).
Schenkel, J. M. et al. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).
Salerno, E. P., Olson, W. C., McSkimming, C., Shea, S. & Slingluff, C. L. Jr. T cells in the human metastatic melanoma microenvironment express site-specific homing receptors and retention integrins. Int. J. Cancer 134, 563–574 (2014).
Ganesan, A. P. et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat. Immunol. 18, 940–950 (2017).
Djenidi, F. et al. CD8+ CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J. Immunol. 194, 3475–3486 (2015).
Li, J., Olshansky, M., Carbone, F. R. & Ma, J. Z. Transcriptional analysis of T cells resident in human skin. PLOS ONE 11, e0148351 (2016).
Milner, J. J. et al. Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours. Nature 552, 253–257 (2017).
Mackay, L. K. et al. T-Box transcription factors combine with the cytokines TGF-beta and IL-15 to control tissue-resident memory T cell fate. Immunity 43, 1101–1111 (2015).
Cyster, J. G. & Schwab, S. R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30, 69–94 (2012).
Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).
Park, S. L., Mackay, L. K. & Gebhardt, T. Distinct recirculation potential of CD69+ CD103− and CD103+ thymic memory CD8+ T cells. Immunol. Cell Biol. 94, 975–980 (2016).
Kumar, B. V. et al. Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites. Cell Rep. 20, 2921–2934 (2017).
Borges da Silva, H. et al. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature 559, 264–268 (2018).
Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl Acad. Sci. USA 111, 5307–5312 (2014).
Richmond, J. M. et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci. Transl Med. 10, eaam7710 (2018).
Van Braeckel-Budimir, N., Varga, S. M., Badovinac, V. P. & Harty, J. T. Repeated antigen exposure extends the durability of influenza-specific lung-resident memory CD8+ T cells and heterosubtypic immunity. Cell Rep. 24, 3374–3382 (2018).
Masopust, D., Vezys, V., Wherry, E. J., Barber, D. L. & Ahmed, R. Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J. Immunol. 176, 2079–2083 (2006).
Khan, T. N., Mooster, J. L., Kilgore, A. M., Osborn, J. F. & Nolz, J. C. Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection. J. Exp. Med. 213, 951–966 (2016).
Schenkel, J. M., Fraser, K. A., Vezys, V. & Masopust, D. Sensing and alarm function of resident memory CD8+ T cells. Nat. Immunol. 14, 509–513 (2013).
Ariotti, S. et al. T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 346, 101–105 (2014).
Casey, K. A. et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J. Immunol. 188, 4866–4875 (2012).
Park, C. O. et al. Staged development of long-lived T cell receptor alphabeta TH17 resident memory T cell population to Candida albicans after skin infection. J. Allergy Clin. Immunol. 142, 647–662 (2017).
Glennie, N. D. et al. Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection. J. Exp. Med. 212, 1405–1414 (2015).
Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).
Sanchez Rodriguez, R. et al. Memory regulatory T cells reside in human skin. J. Clin. Invest. 124, 1027–1036 (2014).
Collins, N. et al. Skin CD4+ memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation. Nat. Commun. 7, 11514 (2016).
Himmelein, S. et al. Circulating herpes simplex type 1 (HSV-1)-specific CD8+ T cells do not access HSV-1 latently infected trigeminal ganglia. Herpesviridae 2, 5 (2011).
Wakim, L. M., Jones, C. M., Gebhardt, T., Preston, C. M. & Carbone, F. R. CD8+ T cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection. Immunol. Cell Biol. 86, 666–675 (2008).
Zhu, J. et al. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J. Exp. Med. 204, 595–603 (2007).
Zhu, J. et al. Immune surveillance by CD8alphaalpha+ skin-resident T cells in human herpes virus infection. Nature 497, 494–497 (2013).
Zhu, J. et al. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nat. Med. 15, 886–892 (2009).
Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).
Thome, J. J. et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159, 814–828 (2014).
Kumar, B. V., Connors, T. J. & Farber, D. L. Human T cell development, localization, and function throughout life. Immunity 48, 202–213 (2018).
MacLeod, A. S. et al. Dendritic epidermal T cells regulate skin antimicrobial barrier function. J. Clin. Invest. 123, 4364–4374 (2013).
Jameson, J. M., Cauvi, G., Witherden, D. A. & Havran, W. L. A keratinocyte-responsive gamma delta TCR is necessary for dendritic epidermal T cell activation by damaged keratinocytes and maintenance in the epidermis. J. Immunol. 172, 3573–3579 (2004).
Jiang, X., Campbell, J. J. & Kupper, T. S. Embryonic trafficking of gammadelta T cells to skin is dependent on E/P selectin ligands and CCR4. Proc. Natl Acad. Sci. USA 107, 7443–7448 (2010).
Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009).
Jameson, J. et al. A role for skin gammadelta T cells in wound repair. Science 296, 747–749 (2002).
Adams, E. J., Gu, S. & Luoma, A. M. Human gamma delta T cells: evolution and ligand recognition. Cell. Immunol. 296, 31–40 (2015).
Cruz, M. S., Diamond, A., Russell, A. & Jameson, J. M. Human alphabeta and gammadelta T cells in skin immunity and disease. Front. Immunol. 9, 1304 (2018).
Jiang, X. et al. Dermal gammadelta T cells do not freely re-circulate out of skin and produce IL-17 to promote neutrophil infiltration during primary contact hypersensitivity. PLOS ONE 12, e0169397 (2017).
Scharschmidt, T. C. et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity 43, 1011–1021 (2015).
Strid, J. et al. Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat. Immunol. 9, 146–154 (2008).
Kashem, S. W. et al. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity 43, 515–526 (2015).
Cai, Y. et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 35, 596–610 (2011).
Komori, H. K. et al. Cutting edge: dendritic epidermal gammadelta T cell ligands are rapidly and locally expressed by keratinocytes following cutaneous wounding. J. Immunol. 188, 2972–2976 (2012).
Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).
Van Rhijn, I., Godfrey, D. I., Rossjohn, J. & Moody, D. B. Lipid and small-molecule display by CD1 and MR1. Nat. Rev. Immunol. 15, 643–654 (2015).
Dougan, S. K., Kaser, A. & Blumberg, R. S. CD1 expression on antigen-presenting cells. Curr. Top. Microbiol. Immunol. 314, 113–141 (2007).
Mori, L., Lepore, M. & De Libero, G. The immunology of CD1- and MR1-restricted T cells. Annu. Rev. Immunol. 34, 479–510 (2016).
Godfrey, D. I., Stankovic, S. & Baxter, A. G. Raising the NKT cell family. Nat. Immunol. 11, 197–206 (2010).
de Jong, A. et al. CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat. Immunol. 15, 177–185 (2014).
de Jong, A. et al. CD1a-autoreactive T cells are a normal component of the human alphabeta T cell repertoire. Nat. Immunol. 11, 1102–1109 (2010).
Bourgeois, E. A. et al. Bee venom processes human skin lipids for presentation by CD1a. J. Exp. Med. 212, 149–163 (2015).
Cheung, K. L. et al. Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a. J. Exp. Med. 213, 2399–2412 (2016).
Kim, J. H. et al. CD1a on Langerhans cells controls inflammatory skin disease. Nat. Immunol. 17, 1159–1166 (2016).
Vincent, M. S. et al. CD1-dependent dendritic cell instruction. Nat. Immunol. 3, 1163–1168 (2002).
Grice, E. A. et al. A diversity profile of the human skin microbiota. Genome Res. 18, 1043–1050 (2008).
Grice, E. A. & Segre, J. A. The skin microbiome. Nat. Rev. Microbiol. 9, 244–253 (2011).
Scharschmidt, T. C. et al. Commensal microbes and hair follicle morphogenesis coordinately drive Treg migration into neonatal skin. Cell Host Microbe 21, 467–477 (2017).
Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012).
Naik, S. et al. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015).
Saoudi, A., Seddon, B., Heath, V., Fowell, D. & Mason, D. The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset. Immunol. Rev. 149, 195–216 (1996).
Singh, B. et al. Control of intestinal inflammation by regulatory T cells. Immunol. Rev. 182, 190–200 (2001).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).
Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+ CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).
Seneschal, J., Clark, R. A., Gehad, A., Baecher-Allan, C. M. & Kupper, T. S. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36, 873–884 (2012).
Hirahara, K. et al. The majority of human peripheral blood CD4+CD25highFoxp3+ regulatory T cells bear functional skin-homing receptors. J. Immunol. 177, 4488–4494 (2006).
Rosenblum, M. D. et al. Response to self antigen imprints regulatory memory in tissues. Nature 480, 538–542 (2011).
van der Veeken, J. et al. Memory of inflammation in regulatory T cells. Cell 166, 977–990 (2016).
Miragaia, R. J. et al. Single cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity 50, 493–504 (2017).
Zemmour, D. et al. Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat. Immunol. 19, 291–301 (2018).
DiSpirito, J. R. et al. Molecular diversification of regulatory T cells in nonlymphoid tissues. Sci. Immunol. 3, eaat5861 (2018).
Sather, B. D. et al. Altering the distribution of Foxp3+ regulatory T cells results in tissue-specific inflammatory disease. J. Exp. Med. 204, 1335–1347 (2007).
Ali, N. et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129 (2017).
Arpaia, N. et al. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078–1089 (2015).
Nosbaum, A. et al. Cutting edge: regulatory T cells facilitate cutaneous wound healing. J. Immunol. 196, 2010–2014 (2016).
Nestle, F. O., Kaplan, D. H. & Barker, J. Psoriasis. N. Engl. J. Med. 361, 496–509 (2009).
Lowes, M. A., Bowcock, A. M. & Krueger, J. G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007).
Nair, R. P. et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am. J. Hum. Genet. 78, 827–851 (2006).
Trembath, R. C. et al. Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. Hum. Mol. Genet. 6, 813–820 (1997).
Gottlieb, S. L. et al. Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat. Med. 1, 442–447 (1995).
Zheng, Y. et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).
Griffiths, C. E. et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N. Engl. J. Med. 362, 118–128 (2010).
Lowes, M. A. et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J. Invest. Dermatol. 128, 1207–1211 (2008).
Papp, K. A. et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N. Engl. J. Med. 366, 1181–1189 (2012).
Papp, K. et al. Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br. J. Dermatol. 173, 930–939 (2015).
Papp, K. A. et al. Anti-IL-17 receptor antibody AMG 827 leads to rapid clinical response in subjects with moderate to severe psoriasis: results from a phase I, randomized, placebo-controlled trial. J. Invest. Dermatol. 132, 2466–2469 (2012).
Leonardi, C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N. Engl. J. Med. 366, 1190–1199 (2012).
Sofen, H. et al. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J. Allergy Clin. Immunol. 133, 1032–1040 (2014).
Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).
Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).
Nair, R. P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat. Genet. 41, 199–204 (2009).
Nair, R. P. et al. Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J. Invest. Dermatol. 128, 1653–1661 (2008).
Zaba, L. C., Krueger, J. G. & Lowes, M. A. Resident and “inflammatory” dendritic cells in human skin. J. Invest. Dermatol. 129, 302–308 (2009).
Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).
Ciofani, M. et al. A validated regulatory network for Th17 cell specification. Cell 151, 289–303 (2012).
Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).
Fobelo Lozano, M. J., Serrano Gimenez, R. & Castro Fernandez, M. Emergence of inflammatory bowel disease during treatment with secukinumab. J. Crohns Colitis 12, 1131–1133 (2018).
Matos, T. R. et al. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones. J. Clin. Invest. 127, 4031–4041 (2017).
Deckers, I. A. et al. Investigating international time trends in the incidence and prevalence of atopic eczema 1990–2010: a systematic review of epidemiological studies. PLOS ONE 7, e39803 (2012).
Guttman-Yassky, E., Nograles, K. E. & Krueger, J. G. Contrasting pathogenesis of atopic dermatitis and psoriasis — part II: immune cell subsets and therapeutic concepts. J. Allergy Clin. Immunol. 127, 1420–1432 (2011).
Guttman-Yassky, E., Nograles, K. E. & Krueger, J. G. Contrasting pathogenesis of atopic dermatitis and psoriasis — part I: clinical and pathologic concepts. J. Allergy Clin. Immunol. 127, 1110–1118 (2011).
Brunner, P. M., Guttman-Yassky, E. & Leung, D. Y. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J. Allergy Clin. Immunol. 139, S65–S76 (2017).
Czarnowicki, T., Krueger, J. G. & Guttman-Yassky, E. Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications. J. Allergy Clin. Immunol. Pract. 2, 371–379 (2014).
McGrath, J. A. & Uitto, J. The filaggrin story: novel insights into skin-barrier function and disease. Trends Mol. Med. 14, 20–27 (2008).
Esaki, H. et al. Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J. Allergy Clin. Immunol. 138, 1639–1651 (2016).
Jarrett, R. et al. Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase. Sci. Transl Med. 8, 325ra318 (2016).
Gutowska-Owsiak, D., Schaupp, A. L., Salimi, M., Taylor, S. & Ogg, G. S. Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes. Br. J. Dermatol. 165, 492–498 (2011).
Islam, S. A. et al. Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ T(H)2 cells. Nat. Immunol. 12, 167–177 (2011).
Soumelis, V. et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680 (2002).
Cevikbas, F. et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J. Allergy Clin. Immunol. 133, 448–460 (2014).
Simpson, E. L. et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N. Engl. J. Med. 375, 2335–2348 (2016).
Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005).
Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015).
Guttman-Yassky, E. et al. Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: a randomized, double-blind, phase 2a trial. J. Am. Acad. Dermatol. 78, 872–881 (2018).
Mirzoyev, S. A., Schrum, A. G., Davis, M. D. P. & Torgerson, R. R. Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990–2009. J. Invest. Dermatol. 134, 1141–1142 (2014).
Strazzulla, L. C. et al. Alopecia areata: disease characteristics, clinical evaluation, and new perspectives on pathogenesis. J. Am. Acad. Dermatol. 78, 1–12 (2018).
Pratt, C. H. et al. Alopecia areata. Nat. Rev. Dis. Primers 3, 17011 (2017).
Petukhova, L. et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 466, 113–117 (2010).
Betz, R. C. et al. Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci. Nat. Commun. 6, 5966 (2015).
Gilhar, A., Etzioni, A. & Paus, R. Alopecia areata. N. Engl. J. Med. 366, 1515–1525 (2012).
Dressel, D. et al. Alopecia areata but not androgenetic alopecia is characterized by a restricted and oligoclonal T cell receptor-repertoire among infiltrating lymphocytes. J. Cutan. Pathol. 24, 164–168 (1997).
Gilhar, A., Ullmann, Y., Berkutzki, T., Assy, B. & Kalish, R. S. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J. Clin. Invest. 101, 62–67 (1998).
Xing, L. et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat. Med. 20, 1043–1049 (2014).
Liu, L. Y., Craiglow, B. G., Dai, F. & King, B. A. Tofacitinib for the treatment of severe alopecia areata and variants: a study of 90 patients. J. Am. Acad. Dermatol. 76, 22–28 (2017).
Strazzulla, L. C. et al. Alopecia areata: an appraisal of new treatment approaches and overview of current therapies. J. Am. Acad. Dermatol. 78, 15–24 (2018).
Taieb, A. & Picardo, M. Clinical practice. Vitiligo. N. Engl. J. Med. 360, 160–169 (2009).
Frisoli, M. L. & Harris, J. E. Vitiligo: mechanistic insights lead to novel treatments. J. Allergy Clin. Immunol. 140, 654–662 (2017).
van den Boorn, J. G. et al. Autoimmune destruction of skin melanocytes by perilesional T cells from vitiligo patients. J. Invest. Dermatol. 129, 2220–2232 (2009).
Jimbow, K., Chen, H., Park, J. S. & Thomas, P. D. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br. J. Dermatol. 144, 55–65 (2001).
Speeckaert, R. et al. Critical appraisal of the oxidative stress pathway in vitiligo: a systematic review and meta-analysis. J. Eur. Acad. Dermatol. Venereol. 32, 1089–1098 (2018).
Rashighi, M. et al. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci. Transl Med. 6, 223ra223 (2014).
Harris, J. E. et al. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-gamma for autoreactive CD8+ T cell accumulation in the skin. J. Invest. Dermatol. 132, 1869–1876 (2012).
Richmond, J. M. et al. CXCR3 depleting antibodies prevent and reverse vitiligo in mice. J. Invest. Dermatol. 137, 982–985 (2017).
Harris, J. E. et al. Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA). J. Am. Acad. Dermatol. 74, 370–371 (2016).
Craiglow, B. G. & King, B. A. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy. JAMA Dermatol. 151, 1110–1112 (2015).
Rothstein, B. et al. Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib. J. Am. Acad. Dermatol. 76, 1054–1060 (2017).
Cheuk, S. et al. CD49a expression defines tissue-resident CD8+ T cells poised for cytotoxic function in human skin. Immunity 46, 287–300 (2017).
Malik, B. T. et al. Resident memory T cells in the skin mediate durable immunity to melanoma. Sci. Immunol. 2, eaam6346 (2017).
Schwartz, D. M. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 17, 78 (2017).
Blauvelt, A. et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J. Am. Acad. Dermatol. 76, 405–417 (2017).
Papp, K. A. et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N. Engl. J. Med. 376, 1551–1560 (2017).
Timerman, D. et al. Novel application of high-dose rate brachytherapy for severe, recalcitrant palmoplantar pustulosis. Clin. Exp. Dermatol. 41, 498–501 (2016).