γδ T cells in homeostasis and host defence of epithelial barrier tissues

Nature Reviews Immunology

Volumn 17, Issue 12, 2017, Pages 733-745

  Nielsen, Morten M ^a,b   Witherden, Deborah A ^a   Havran, Wendy L ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

BUTYROPHILIN; CD100 PROTEIN; CONCANAVALIN A; CONSTITUTIVE ANDROSTANE RECEPTOR; FIBROBLAST GROWTH FACTOR 10; GAMMA INTERFERON; INTERLEUKIN 1 RECEPTOR; INTERLEUKIN 17; INTERLEUKIN 2; INTERLEUKIN 5; JUNCTIONAL ADHESION MOLECULE; KERATINOCYTE GROWTH FACTOR; NATURAL KILLER CELL RECEPTOR NKG2A; NATURAL KILLER CELL RECEPTOR NKG2D; OCCLUDIN; SEMAPHORIN; SOMATOMEDIN C; TOLL LIKE RECEPTOR 2; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG; BIOLOGICAL MARKER; LYMPHOCYTE ANTIGEN RECEPTOR;

ALPHA BETA T LYMPHOCYTE; BTNL GENE; COMMENSAL; CYTOKINE PRODUCTION; CYTOTOXICITY; DENDRITIC EPIDERMAL GAMMA DELTA T LYMPHOCYTE; GAMMA DELTA INTRAEPITHELIAL LYMPHOCYTE; GAMMA DELTA T LYMPHOCYTE; GENETIC REGULATION; HOMEOSTASIS; HOST RESISTANCE; HUMAN; INTESTINE EPITHELIUM; INTESTINE FLORA; INTESTINE MUCOSA PERMEABILITY; LEISHMANIASIS; LYMPHOCYTE MIGRATION; LYMPHOCYTE PROLIFERATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; SKIN EPITHELIUM; SKIN FLORA; STAPHYLOCOCCUS EPIDERMIDIS; STAPHYLOCOCCUS INFECTION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TISSUE HOMEOSTASIS; TISSUE REPAIR; WOUND HEALING; ANIMAL; CELL DIFFERENTIATION; CYTOLOGY; EPITHELIUM; GENE EXPRESSION REGULATION; GENETICS; HOST PATHOGEN INTERACTION; IMMUNOLOGY; INTESTINE MUCOSA; LYMPHOCYTE; METABOLISM; MICROBIOLOGY; MUCOSAL-ASSOCIATED INVARIANT T CELL; PHYSIOLOGY;

ANIMALS; BIOMARKERS; BUTYROPHILINS; CELL DIFFERENTIATION; EPITHELIUM; GENE EXPRESSION REGULATION; HOMEOSTASIS; HOST-PATHOGEN INTERACTIONS; HUMANS; INTESTINAL MUCOSA; INTRAEPITHELIAL LYMPHOCYTES; MUCOSAL-ASSOCIATED INVARIANT T CELLS; RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA; SIGNAL TRANSDUCTION;

EID: 85034851574     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri.2017.101     Document Type: Review

References (144)

1. Chien, Y. H., Meyer, C. & Bonneville, M. Gammadelta T cells: first line of defense and beyond. Annu. Rev. Immunol. 32, 121-155 (2014).
2. Jameson, J. M., Sharp, L. L., Witherden, D. A. & Havran, W. L. Regulation of skin cell homeostasis by gamma delta T cells. Front. Biosci. 9, 2640-2651 (2004).
3. Roberts, N. & Horsley, V. Developing stratified epithelia: lessons from the epidermis and thymus. Wiley Interdiscip. Rev. Dev. Biol. 3, 389-402 (2014).
4. van der Flier, L. G. & Clevers, H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu. Rev. Physiol. 71, 241-260 (2009).
5. Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445-456 (2011).
6. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268-1273 (2012).
7. Boyden, L. M. et al. Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells. Nat. Genet. 40, 656-662 (2008).
8. Di Marco, B. R. et al. Epithelia use butyrophilin-like molecules to shape organ-specific gammadelta T cell compartments. Cell 167, 203-218 (2016).
9. Rhodes, D. A., Reith, W. & Trowsdale, J. Regulation of immunity by butyrophilins. Annu. Rev. Immunol. 34, 151-172 (2016).
10. Crosnier, C., Stamataki, D. & Lewis, J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nat. Rev. Genet. 7, 349-359 (2006).
11. Fuchs, E. Epithelial skin biology: three decades of developmental biology, a hundred questions answered and a thousand new ones to address. Curr. Top. Dev. Biol. 116, 357-374 (2016).
12. Pasparakis, M., Haase, I. & Nestle, F. O. Mechanisms regulating skin immunity and inflammation. Nat. Rev Immunol. 14, 289-301 (2014).
13. Havran, W. L. & Jameson, J. M. Epidermal T cells and wound healing. J. Immunol. 184, 5423-5428 (2010).
14. Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743-750 (2009).
15. Belkaid, Y. & Tamoutounour, S. The influence of skin microorganisms on cutaneous immunity. Nat. Rev. Immunol. 16, 353-366 (2016).
16. Veldhoen, M. & Brucklacher-Waldert, V. Dietary influences on intestinal immunity. Nat. Rev. Immunol. 12, 696-708 (2012).
17. Qiu, Y. et al. Disturbance of intraepithelial lymphocytes in a murine model of acute intestinal ischemia/reperfusion. J. Mol. Histol. 45, 217-227 (2014).
18. Havran, W. L., Jameson, J. M. & Witherden, D. A. Epithelial cells and their neighbors. III. Interactions between intraepithelial lymphocytes and neighboring epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G627-G630 (2005).
19. Wiest, D. L. Development of gammadelta T Cells, the special-force soldiers of the immune system. Methods Mol. Biol. 1323, 23-32 (2016).
20. + dendritic epidermal cells of adult mice from fetal thymic precursors. Nature 344, 68-70 (1990).
21. Itohara, S. et al. Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343, 754-757 (1990).
22. Garman, R. D., Doherty, P. J. & Raulet, D. H. Diversity, rearrangement, and expression of murine T cell gamma genes. Cell 45, 733-742 (1986).
23. Heilig, J. S. & Tonegawa, S. Diversity of murine gamma genes and expression in fetal and adult T lymphocytes. Nature 322, 836-840 (1986).
24. + dendritic epidermal cells. Cell 55, 837-847 (1988).
25. Havran, W. L. & Allison, J. P. Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335, 443-445 (1988).
26. Takagaki, Y., DeCloux, A., Bonneville, M. & Tonegawa, S. Diversity of gamma delta T-cell receptors on murine intestinal intra-epithelial lymphocytes. Nature 339, 712-714 (1989).
27. Cheroutre, H. & Lambolez, F. The thymus chapter in the life of gut-specific intra epithelial lymphocytes. Curr. Opin. Immunol. 20, 185-191 (2008).
28. Ishikawa, H. et al. Curriculum vitae of intestinal intraepithelial T cells: their developmental and behavioral characteristics. Immunol. Rev. 215, 154-165 (2007).
29. Maki, K. et al. Interleukin 7 receptor-deficient mice lack gammadelta T cells. Proc. Natl Acad. Sci. USA 93, 7172-7177 (1996).
30. Maki, K., Sunaga, S. & Ikuta, K. The V-J recombination of T cell receptor-gamma genes is blocked in interleukin-7 receptor-deficient mice. J. Exp. Med. 184, 2423-2427 (1996).
31. + intraepithelial lymphocytes. J. Immunol. 190, 6173-6179 (2013).
32. Kang, J. et al. STAT5 is required for thymopoiesis in a development stage-specific manner. J. Immunol. 173, 2307-2314 (2004).
33. Ye, S. K. et al. The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation. Immunity 15, 813-823 (2001).
34. Zhao, H., Nguyen, H. & Kang, J. Interleukin 15 controls the generation of the restricted T cell receptor repertoire of gamma delta intestinal intraepithelial lymphocytes. Nat. Immunol. 6, 1263-1271 (2005).
35. De Creus, A. et al. Developmental and functional defects of thymic and epidermal V gamma 3 cells in IL-15-deficient and IFN regulatory factor-1-deficient mice. J. Immunol. 168, 6486-6493 (2002).
36. Kawai, K. et al. Requirement of the IL-2 receptor beta chain for the development of Vgamma3 dendritic epidermal T cells. J. Invest. Dermatol. 110, 961-965 (1998).
37. Kennedy, M. K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191, 771-780 (2000).
38. Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669-676 (1998).
39. Schluns, K. S. et al. Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor alpha expression. Proc. Natl Acad. Sci. USA 101, 5616-5621 (2004).
40. Kadow, S. et al. Aryl hydrocarbon receptor is critical for homeostasis of invariant gammadelta T cells in the murine epidermis. J. Immunol. 187, 3104-3110 (2011).
41. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629-640 (2011).
42. Hooper, L. V. You AhR what you eat: linking diet and immunity. Cell 147, 489-491 (2011).
43. Stange, J. & Veldhoen, M. The aryl hydrocarbon receptor in innate T cell immunity. Semin. Immunopathol. 35, 645-655 (2013).
44. Girardi, M., Lewis, J. M., Filler, R. B., Hayday, A. C. & Tigelaar, R. E. Environmentally responsive and reversible regulation of epidermal barrier function by gammadelta T cells. J. Invest. Dermatol. 126, 808-814 (2006).
45. Itohara, S. et al. T cell receptor delta gene mutant mice: independent generation of alpha beta T cells and programmed rearrangements of gamma delta TCR genes. Cell 72, 337-348 (1993).
46. Xia, M. et al. Differential roles of IL-2-inducible T cell kinase-mediated TCR signals in tissue-specific localization and maintenance of skin intraepithelial T cells. J. Immunol. 184, 6807-6814 (2010).
47. 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).
48. Jin, Y. et al. Cutting edge: intrinsic programming of thymic gammadeltaT cells for specific peripheral tissue localization. J. Immunol. 185, 7156-7160 (2010).
49. Xiong, N., Kang, C. & Raulet, D. H. Positive selection of dendritic epidermal gammadelta T cell precursors in the fetal thymus determines expression of skin-homing receptors. Immunity 21, 121-131 (2004).
50. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355-360 (2004).
51. Austrup, F. et al. P-and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues. Nature 385, 81-83 (1997).
52. Morales, J. et al. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc. Natl Acad. Sci. USA 96, 14470-14475 (1999).
53. Jin, Y., Xia, M., Sun, A., Saylor, C. M. & Xiong, N. CCR10 is important for the development of skin-specific gammadeltaT cells by regulating their migration and location. J. Immunol. 185, 5723-5731 (2010).
54. Kunisawa, J. et al. Sphingosine 1-phosphate dependence in the regulation of lymphocyte trafficking to the gut epithelium. J. Exp. Med. 204, 2335-2348 (2007).
55. Ogata, M. & Itoh, T. Gamma/delta intraepithelial lymphocytes in the mouse small intestine. Anat. Sci. Int. 91, 301-312 (2016).
56. + recent thymic emigrants home to and efficiently repopulate the small intestine epithelium. Nat. Immunol. 7, 482-488 (2006).
57. Wurbel, M. A. et al. The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double-and single-positive thymocytes expressing the TECK receptor CCR9. Eur. J. Immunol. 30, 262-271 (2000).
58. Wurbel, M. A. et al. Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T-and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes. Blood 98, 2626-2632 (2001).
59. Wurbel, M. A., Malissen, M., Guy-Grand, D., Malissen, B. & Campbell, J. J. Impaired accumulation of antigen-specific CD8 lymphocytes in chemokine CCL25-deficient intestinal epithelium and lamina propria. J. Immunol. 178, 7598-7606 (2007).
60. Jensen, K. D., Shin, S. & Chien, Y. H. Cutting edge: gammadelta intraepithelial lymphocytes of the small intestine are not biased toward thymic antigens. J. Immunol. 182, 7348-7351 (2009).
61. Guy-Grand, D. et al. Origin, trafficking, and intraepithelial fate of gut-tropic T cells. J. Exp. Med. 210, 1839-1854 (2013).
62. Chen, Y., Chou, K., Fuchs, E., Havran, W. L. & Boismenu, R. Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc. Natl Acad. Sci. USA 99, 14338-14343 (2002).
63. Jameson, J. et al. A role for skin gammadelta T cells in wound repair. Science 296, 747-749 (2002).
64. Sharp, L. L., Jameson, J. M., Cauvi, G. & Havran, W. L. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat. Immunol. 6, 73-79 (2005).
65. Chodaczek, G., Papanna, V., Zal, M. A. & Zal, T. Body-barrier surveillance by epidermal gammadelta TCRs. Nat. Immunol. 13, 272-282 (2012).
66. Gray, E. E., Suzuki, K. & Cyster, J. G. Cutting edge: identification of a motile IL-17-producing gammadelta T cell population in the dermis. J. Immunol. 186, 6091-6095 (2011).
67. 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).
68. Havran, W. L., Chien, Y. H. & Allison, J. P. Recognition of self antigens by skin-derived T cells with invariant gamma delta antigen receptors. Science 252, 1430-1432 (1991).
69. Boismenu, R. & Havran, W. L. Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266, 1253-1255 (1994).
70. Boismenu, R., Feng, L., Xia, Y. Y., Chang, J. C. & Havran, W. L. Chemokine expression by intraepithelial gamma delta T cells. Implications for the recruitment of inflammatory cells to damaged epithelia. J. Immunol. 157, 985-992 (1996).
71. Jameson, J. & Havran, W. L. Skin gammadelta T-cell functions in homeostasis and wound healing. Immunol. Rev. 215, 114-122 (2007).
72. Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2, 997-1003 (2001).
73. Verdino, P., Witherden, D. A., Havran, W. L. & Wilson, I. A. The molecular interaction of CAR and JAML recruits the central cell signal transducer PI3K. Science 329, 1210-1214 (2010).
74. Witherden, D. A. et al. The junctional adhesion molecule JAML is a costimulatory receptor for epithelial gammadelta T cell activation. Science 329, 1205-1210 (2010).
75. Witherden, D. A. et al. The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal gammadelta T cell function. Immunity 37, 314-325 (2012).
76. Yoshida, S. et al. Involvement of an NKG2D ligand H60c in epidermal dendritic T cell-mediated wound repair. J. Immunol. 188, 3972-3979 (2012).
77. Girardi, M. et al. Regulation of cutaneous malignancy by gammadelta T cells. Science 294, 605-609 (2001).
78. 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).
79. Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938-945 (2015).
80. Silva-Santos, B., Serre, K. & Norell, H. Gammadelta T cells in cancer. Nat. Rev. Immunol. 15, 683-691 (2015).
81. Elbe, A., Foster, C. A. & Stingl, G. T-Cell receptor alpha beta and gamma delta T cells in rat and human skin-are they equivalent? Semin. Immunol. 8, 341-349 (1996).
82. Holtmeier, W. et al. The TCR-delta repertoire in normal human skin is restricted and distinct from the TCR-delta repertoire in the peripheral blood. J. Invest. Dermatol. 116, 275-280 (2001).
83. Edelblum, K. L. et al. Dynamic migration of gammadelta intraepithelial lymphocytes requires occludin. Proc. Natl Acad. Sci. USA 109, 7097-7102 (2012).
84. Komano, H. et al. Homeostatic regulation of intestinal epithelia by intraepithelial gamma delta T cells. Proc. Natl Acad. Sci. USA 92, 6147-6151 (1995).
85. Yang, H., Antony, P. A., Wildhaber, B. E. & Teitelbaum, D. H. Intestinal intraepithelial lymphocyte gamma delta-T cell-derived keratinocyte growth factor modulates epithelial growth in the mouse. J. Immunol. 172, 4151-4158 (2004).
86. + lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection. Gastroenterology 131, 818-829 (2006).
87. Inagaki-Ohara, K. et al. Mucosal T cells bearing TCRgammadelta play a protective role in intestinal inflammation. J. Immunol. 173, 1390-1398 (2004).
88. Meehan, T. F. et al. Protection against colitis by CD100-dependent modulation of intraepithelial gammadelta T lymphocyte function. Mucosal. Immunol. 7, 134-142 (2014).
89. Pazirandeh, A. et al. Multiple phenotypes in adult mice following inactivation of the Coxsackievirus and Adenovirus Receptor (Car) gene. PLoS ONE 6, e20203 (2011).
90. Kuhl, A. A. et al. Aggravation of intestinal inflammation by depletion/deficiency of gammadelta T cells in different types of IBD animal models. J. Leukoc. Biol. 81, 168-175 (2007).
91. + intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. J. Clin. Invest. 118, 281-293 (2008).
92. + T cell repertoire by a thymic stromal determinant. Nat. Immunol. 7, 843-850 (2006).
93. Turchinovich, G. & Hayday, A. C. Skint-1 identifies a common molecular mechanism for the development of interferon-gamma-secreting versus interleukin-17-secreting gammadelta T cells. Immunity 35, 59-68 (2011).
94. Wencker, M. et al. Innate-like T cells straddle innate and adaptive immunity by altering antigen-receptor responsiveness. Nat. Immunol. 15, 80-87 (2014).
95. 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).
96. Bas, A. et al. Butyrophilin-like 1 encodes an enterocyte protein that selectively regulates functional interactions with T lymphocytes. Proc. Natl Acad. Sci. USA 108, 4376-4381 (2011).
97. Keyes, B. E. et al. Impaired epidermal to dendritic T cell signaling slows wound repair in aged skin. Cell 167, 1323-1338 (2016).
98. Barbee, S. D. et al. Skint-1 is a highly specific, unique selecting component for epidermal T cells. Proc. Natl Acad. Sci. USA 108, 3330-3335 (2011).
99. Adams, E. J., Gu, S. & Luoma, A. M. Human gamma delta T cells: evolution and ligand recognition. Cell. Immunol. 296, 31-40 (2015).
100. Rhodes, D. A. et al. Activation of human gammadelta T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor periplakin. J. Immunol. 194, 2390-2398 (2015).
101. Sandstrom, A. et al. The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells. Immunity 40, 490-500 (2014).
102. Vavassori, S. et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human gammadelta T cells. Nat. Immunol. 14, 908-916 (2013).
103. Ceeraz, S., Nowak, E. C. & Noelle, R. J. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 34, 556-563 (2013).
104. Arnett, H. A. et al. BTNL2, a butyrophilin/B7-like molecule, is a negative costimulatory molecule modulated in intestinal inflammation. J. Immunol. 178, 1523-1533 (2007).
105. Nguyen, T., Liu, X. K., Zhang, Y. & Dong, C. BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation. J. Immunol. 176, 7354-7360 (2006).
106. Yamazaki, T. et al. A butyrophilin family member critically inhibits T cell activation. J. Immunol. 185, 5907-5914 (2010).
107. Chapoval, A. I. et al. BTNL8, a butyrophilin-like molecule that costimulates the primary immune response. Mol. Immunol. 56, 819-828 (2013).
108. Levy, M., Kolodziejczyk, A. A., Thaiss, C. A. & Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 17, 219-232 (2017).
109. Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159-169 (2010).
110. Bandeira, A. et al. Localization of gamma/delta T cells to the intestinal epithelium is independent of normal microbial colonization. J. Exp. Med. 172, 239-244 (1990).
111. Moor, K. et al. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature 544, 498-502 (2017).
112. Salzman, N. H., Ghosh, D., Huttner, K. M., Paterson, Y. & Bevins, C. L. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422, 522-526 (2003).
113. Ismail, A. S. et al. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc. Natl Acad. Sci. USA 108, 8743-8748 (2011).
114. Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126-1130 (2006).
115. Mukherjee, S. et al. Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505, 103-107 (2014).
116. Vaishnava, S. et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255-258 (2011).
117. Ismail, A. S., Behrendt, C. L. & Hooper, L. V. Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury. J. Immunol. 182, 3047-3054 (2009).
118. Fahrer, A. M. et al. Attributes of gammadelta intraepithelial lymphocytes as suggested by their transcriptional profile. Proc. Natl Acad. Sci. USA 98, 10261-10266 (2001).
119. + intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 15, 419-434 (2001).
120. + intraepithelial lymphocytes. Science 243, 1716-1718 (1989).
121. Swamy, M. et al. Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance. Nat. Commun. 6, 7090 (2015).
122. Kong, H. H. et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 22, 850-859 (2012).
123. Leyden, J. J., Marples, R. R. & Kligman, A. M. Staphylococcus aureus in the lesions of atopic dermatitis. Br. J. Dermatol. 90, 525-530 (1974).
124. Nakatsuji, T. et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci. Transl Med. http://dx.doi.org/10.1126/scitranslmed.aah4680 (2017).
125. Gao, Z., Tseng, C. H., Strober, B. E., Pei, Z. & Blaser, M. J. Substantial alterations of the cutaneous bacterial biota in psoriatic lesions. PLoS ONE 3, e2719 (2008).
126. Holmes, A. D. Potential role of microorganisms in the pathogenesis of rosacea. J. Am. Acad. Dermatol. 69, 1025-1032 (2013).
127. Lai, Y. et al. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat. Med. 15, 1377-1382 (2009).
128. Lai, Y. et al. Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. J. Invest. Dermatol. 130, 2211-2221 (2010).
129. Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115-1119 (2012).
130. Lai, Y. et al. The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury. Immunity 37, 74-84 (2012).
131. MacLeod, A. S. et al. Dendritic epidermal T cells regulate skin antimicrobial barrier function. J. Clin. Invest. 123, 4364-4374 (2013).
132. Nielsen, M. M. et al. IL-1beta-dependent activation of dendritic epidermal T cells in contact hypersensitivity. J. Immunol. 192, 2975-2983 (2014).
133. Cai, Y. et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 35, 596-610 (2011).
134. O'Brien, R. L. & Born, W. K. Dermal gammadelta T cells-What have we learned? Cell. Immunol. 296, 62-69 (2015).
135. Nakatsuji, T. et al. The microbiome extends to subepidermal compartments of normal skin. Nat. Commun. 4, 1431 (2013).
136. Cho, J. S. et al. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J. Clin. Invest. 120, 1762-1773 (2010).
137. Leclercq, G. & Plum, J. Stimulation of TCR V gamma 3 cells by gram-negative bacteria. J. Immunol. 154, 5313-5319 (1995).
138. + epidermal cells. J. Invest. Dermatol. 91, 62-68 (1988).
139. + dendritic epidermal cells in mice: precursor frequency analysis and cloning of concanavalin A-reactive cells. J. Invest. Dermatol. 90, 671-678 (1988).
140. Gao, Y. et al. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J. Exp. Med. 198, 433-442 (2003).
141. Ibusuki, A. et al. NKG2D triggers cytotoxicity in murine epidermal gammadelta T cells via PI3K-dependent, Syk/ZAP70-independent signaling pathway. J. Invest. Dermatol. 134, 396-404 (2014).
142. Zhang, M. et al. Oral antibiotic treatment induces skin microbiota dysbiosis and influences wound healing. Microb. Ecol. 69, 415-421 (2015).
143. Canesso, M. C. et al. Skin wound healing is accelerated and scarless in the absence of commensal microbiota. J. Immunol. 193, 5171-5180 (2014).
144. Nestle, F. O., Di, M. P., Qin, J. Z. & Nickoloff, B. J. Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9, 679-691 (2009).