Although sparse among circulating T cells, certain subsets of γδ T cells are present in much higher numbers, constituting between 10 and 100% of the T cells in epithelial tissues, such as the epidermis of the skin and the gastrointestinal tract, and show unique effector functions.
Epithelial-resident γδ T cells have vital roles in tissue homeostasis and re-epithelialization following tissue damage and are thus crucial to the upkeep of epithelial barrier function and host survival.
New co-stimulating receptor–ligand pairs have been identified that drive the activation and effector function of epithelial-resident γδ T cells and the timely return to steady-state conditions following tissue injury.
Butyrophilin-like (BTNL) molecules are part of the B7 family of accessory molecules, and immune-modulatory functions for individual BTNL molecules exist in both humans and mice. Although the precise mechanism remains unknown, the specific expression of individual BTNL family members in epithelial tissues selectively shapes and expands epithelial-specific γδ T cell repertoires.
Epithelial-resident γδ T cell subsets are uniquely positioned to mediate host microbial tolerance while at the same time retaining the ability to mount a rapid response against invading pathogens and thus provide early protection against pathogen entry.
Epithelial surfaces line the body and provide a crucial interface between the body and the external environment. Tissue-resident epithelial γδ T cells represent a major T cell population in the epithelial tissues and are ideally positioned to carry out barrier surveillance and aid in tissue homeostasis and repair. In this Review, we focus on the intraepithelial γδ T cell compartment of the two largest epithelial tissues in the body — namely, the epidermis and the intestine — and provide a comprehensive overview of the crucial contributions of intraepithelial γδ T cells to tissue integrity and repair, host homeostasis and protection in the context of the symbiotic relationship with the microbiome and during pathogen clearance. Finally, we describe epithelium-specific butyrophilin-like molecules and briefly review their emerging role in selectively shaping and regulating epidermal and intestinal γδ T cell repertoires.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Signal Transduction and Targeted Therapy Open Access 22 November 2023
Vγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males
Nature Communications Open Access 18 July 2023
British Journal of Cancer Open Access 13 June 2023
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Chien, Y. H., Meyer, C. & Bonneville, M. Gammadelta T cells: first line of defense and beyond. Annu. Rev. Immunol. 32, 121–155 (2014).
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).
Roberts, N. & Horsley, V. Developing stratified epithelia: lessons from the epidermis and thymus. Wiley Interdiscip. Rev. Dev. Biol. 3, 389–402 (2014).
van der Flier, L. G. & Clevers, H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu. Rev. Physiol. 71, 241–260 (2009).
Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).
Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).
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). This study investigates the underlying cause of the lack of DETCs in FVB.Tac mice, identifies the Skint family of genes and shows that Skint1 mediates DETC precursor maturation in the thymus.
Di Marco, B. R. et al. Epithelia use butyrophilin-like molecules to shape organ-specific gammadelta T cell compartments. Cell 167, 203–218 (2016). This paper shows that timely expression of specific BTNL molecules by postmitotic enterocytes in the villi selectively shapes and regulates the intestinal γδ IEL compartment.
Rhodes, D. A., Reith, W. & Trowsdale, J. Regulation of immunity by butyrophilins. Annu. Rev. Immunol. 34, 151–172 (2016).
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).
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).
Pasparakis, M., Haase, I. & Nestle, F. O. Mechanisms regulating skin immunity and inflammation. Nat. Rev. Immunol. 14, 289–301 (2014).
Havran, W. L. & Jameson, J. M. Epidermal T cells and wound healing. J. Immunol. 184, 5423–5428 (2010).
Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009). This paper shows that human epidermal γδ and αβ T cells exhibit effector functions similar to those of DETCs during wound healing by producing epithelial growth factors, and it also shows that when isolated from chronic nonhealing wounds, these cells are nonresponsive to stimuli.
Belkaid, Y. & Tamoutounour, S. The influence of skin microorganisms on cutaneous immunity. Nat. Rev. Immunol. 16, 353–366 (2016).
Veldhoen, M. & Brucklacher-Waldert, V. Dietary influences on intestinal immunity. Nat. Rev. Immunol. 12, 696–708 (2012).
Qiu, Y. et al. Disturbance of intraepithelial lymphocytes in a murine model of acute intestinal ischemia/reperfusion. J. Mol. Histol. 45, 217–227 (2014).
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).
Wiest, D. L. Development of gammadelta T Cells, the special-force soldiers of the immune system. Methods Mol. Biol. 1323, 23–32 (2016).
Havran, W. L. & Allison, J. P. Origin of Thy-1+ dendritic epidermal cells of adult mice from fetal thymic precursors. Nature 344, 68–70 (1990).
Itohara, S. et al. Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343, 754–757 (1990).
Garman, R. D., Doherty, P. J. & Raulet, D. H. Diversity, rearrangement, and expression of murine T cell gamma genes. Cell 45, 733–742 (1986).
Heilig, J. S. & Tonegawa, S. Diversity of murine gamma genes and expression in fetal and adult T lymphocytes. Nature 322, 836–840 (1986).
Asarnow, D. M. et al. Limited diversity of gamma delta antigen receptor genes of Thy-1+ dendritic epidermal cells. Cell 55, 837–847 (1988).
Havran, W. L. & Allison, J. P. Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335, 443–445 (1988).
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).
Cheroutre, H. & Lambolez, F. The thymus chapter in the life of gut-specific intra epithelial lymphocytes. Curr. Opin. Immunol. 20, 185–191 (2008).
Ishikawa, H. et al. Curriculum vitae of intestinal intraepithelial T cells: their developmental and behavioral characteristics. Immunol. Rev. 215, 154–165 (2007).
Maki, K. et al. Interleukin 7 receptor-deficient mice lack gammadelta T cells. Proc. Natl Acad. Sci. USA 93, 7172–7177 (1996).
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).
Shitara, S. et al. IL-7 produced by thymic epithelial cells plays a major role in the development of thymocytes and TCRgammadelta+ intraepithelial lymphocytes. J. Immunol. 190, 6173–6179 (2013).
Kang, J. et al. STAT5 is required for thymopoiesis in a development stage-specific manner. J. Immunol. 173, 2307–2314 (2004).
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).
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).
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).
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).
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).
Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669–676 (1998).
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).
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).
Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).
Hooper, L. V. You AhR what you eat: linking diet and immunity. Cell 147, 489–491 (2011).
Stange, J. & Veldhoen, M. The aryl hydrocarbon receptor in innate T cell immunity. Semin. Immunopathol. 35, 645–655 (2013).
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).
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).
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).
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).
Jin, Y. et al. Cutting edge: intrinsic programming of thymic gammadeltaT cells for specific peripheral tissue localization. J. Immunol. 185, 7156–7160 (2010).
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).
Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).
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).
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).
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).
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).
Ogata, M. & Itoh, T. Gamma/delta intraepithelial lymphocytes in the mouse small intestine. Anat. Sci. Int. 91, 301–312 (2016).
Staton, T. L. et al. CD8+ recent thymic emigrants home to and efficiently repopulate the small intestine epithelium. Nat. Immunol. 7, 482–488 (2006).
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).
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).
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).
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).
Guy-Grand, D. et al. Origin, trafficking, and intraepithelial fate of gut-tropic T cells. J. Exp. Med. 210, 1839–1854 (2013).
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). Using the DSS model of induced colonic damage, this paper shows that intestinal γδ IELs aid in preserving the integrity of damaged epithelia by providing localized delivery of KGF.
Jameson, J. et al. A role for skin gammadelta T cells in wound repair. Science 296, 747–749 (2002). This paper was the first to report that DETCs are crucial for proper wound healing through the production of KGF and KGF2.
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).
Chodaczek, G., Papanna, V., Zal, M. A. & Zal, T. Body-barrier surveillance by epidermal gammadelta TCRs. Nat. Immunol. 13, 272–282 (2012).
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).
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).
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).
Boismenu, R. & Havran, W. L. Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266, 1253–1255 (1994).
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).
Jameson, J. & Havran, W. L. Skin gammadelta T-cell functions in homeostasis and wound healing. Immunol. Rev. 215, 114–122 (2007).
Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2, 997–1003 (2001).
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).
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). This paper identifies JAML expression by DETCs and intestinal γδ IELs and shows that JAML–CAR interactions provide essential co-stimulatory stimuli to promote DETC activation and effector function in response to stressed and damaged tissue.
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).
Yoshida, S. et al. Involvement of an NKG2D ligand H60c in epidermal dendritic T cell-mediated wound repair. J. Immunol. 188, 3972–3979 (2012).
Girardi, M. et al. Regulation of cutaneous malignancy by gammadelta T cells. Science 294, 605–609 (2001).
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).
Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).
Silva-Santos, B., Serre, K. & Norell, H. Gammadelta T cells in cancer. Nat. Rev. Immunol. 15, 683–691 (2015).
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).
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).
Edelblum, K. L. et al. Dynamic migration of gammadelta intraepithelial lymphocytes requires occludin. Proc. Natl Acad. Sci. USA 109, 7097–7102 (2012).
Komano, H. et al. Homeostatic regulation of intestinal epithelia by intraepithelial gamma delta T cells. Proc. Natl Acad. Sci. USA 92, 6147–6151 (1995).
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).
Dalton, J. E. et al. Intraepithelial gammadelta+ lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection. Gastroenterology 131, 818–829 (2006).
Inagaki-Ohara, K. et al. Mucosal T cells bearing TCRgammadelta play a protective role in intestinal inflammation. J. Immunol. 173, 1390–1398 (2004).
Meehan, T. F. et al. Protection against colitis by CD100-dependent modulation of intraepithelial gammadelta T lymphocyte function. Mucosal. Immunol. 7, 134–142 (2014).
Pazirandeh, A. et al. Multiple phenotypes in adult mice following inactivation of the Coxsackievirus and Adenovirus Receptor (Car) gene. PLoS ONE 6, e20203 (2011).
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).
Bhagat, G. et al. Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. J. Clin. Invest. 118, 281–293 (2008).
Lewis, J. M. et al. Selection of the cutaneous intraepithelial gammadelta+ T cell repertoire by a thymic stromal determinant. Nat. Immunol. 7, 843–850 (2006).
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).
Wencker, M. et al. Innate-like T cells straddle innate and adaptive immunity by altering antigen-receptor responsiveness. Nat. Immunol. 15, 80–87 (2014).
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).
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).
Keyes, B. E. et al. Impaired epidermal to dendritic T cell signaling slows wound repair in aged skin. Cell 167, 1323–1338 (2016). This paper identifies important roles for Skint3 and Skint9 expression by basal keratinocytes in orchestrating DETC activation and/or maintenance and wound healing.
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).
Adams, E. J., Gu, S. & Luoma, A. M. Human gamma delta T cells: evolution and ligand recognition. Cell. Immunol. 296, 31–40 (2015).
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).
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).
Vavassori, S. et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human gammadelta T cells. Nat. Immunol. 14, 908–916 (2013).
Ceeraz, S., Nowak, E. C. & Noelle, R. J. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 34, 556–563 (2013).
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).
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).
Yamazaki, T. et al. A butyrophilin family member critically inhibits T cell activation. J. Immunol. 185, 5907–5914 (2010).
Chapoval, A. I. et al. BTNL8, a butyrophilin-like molecule that costimulates the primary immune response. Mol. Immunol. 56, 819–828 (2013).
Levy, M., Kolodziejczyk, A. A., Thaiss, C. A. & Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 17, 219–232 (2017).
Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159–169 (2010).
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). This paper was the first to report that γδ IEL numbers are unaffected in germ-free mice, indicating that the intestinal microbiota has little to no effect on maintaining γδ IEL homeostatic numbers.
Moor, K. et al. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature 544, 498–502 (2017).
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).
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). This study identifies that small-intestinal γδ IELs produce AMPs in response to intestine-resident bacteria and that this response is driven through an intestinal epithelial cell-intrinsic MYD88 pathway and, together with reference 117, shows that intestinal γδ IELs provide early protection of intestinal tissue against resident bacteria.
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).
Mukherjee, S. et al. Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505, 103–107 (2014).
Vaishnava, S. et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011).
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). This paper was the first to reveal a dialogue between commensal bacteria and colonic γδ IELs, showing that the microbiota regulates key components of the activation programme of γδ IELs when responding to tissue damage.
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).
Shires, J., Theodoridis, E. & Hayday, A. C. Biological insights into TCRgammadelta+ and TCRalphabeta+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 15, 419–434 (2001).
Lefrancois, L. & Goodman, T. In vivo modulation of cytolytic activity and Thy-1 expression in TCR-gammadelta+ intraepithelial lymphocytes. Science 243, 1716–1718 (1989).
Swamy, M. et al. Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance. Nat. Commun. 6, 7090 (2015). This paper finds that activated small-intestinal γδ IELs can direct the intestinal epithelial antiviral response through the production of type I and III IFNs.
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).
Leyden, J. J., Marples, R. R. & Kligman, A. M. Staphylococcus aureus in the lesions of atopic dermatitis. Br. J. Dermatol. 90, 525–530 (1974).
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).
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).
Holmes, A. D. Potential role of microorganisms in the pathogenesis of rosacea. J. Am. Acad. Dermatol. 69, 1025–1032 (2013).
Lai, Y. et al. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat. Med. 15, 1377–1382 (2009). This paper was the first to identify that S. epidermis carries out host-beneficial functions to reduce keratinocyte production of pro-inflammatory cytokines by producing small molecules that act on TLR2 to limit a TLR3-induced inflammatory response.
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).
Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012). This paper identifies that protective immunity against skin pathogens depends on the skin microbiota and also shows that S. epidermis can tune the effector response of skin-residing T cells by regulating IL-1 receptor signalling.
Lai, Y. et al. The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury. Immunity 37, 74–84 (2012). This paper identifies mouse REG3γ and human REG3α as crucial mediators of keratinocyte differentiation and survival during wound healing and shows that these molecules are regulated by IL-17A receptor signalling.
MacLeod, A. S. et al. Dendritic epidermal T cells regulate skin antimicrobial barrier function. J. Clin. Invest. 123, 4364–4374 (2013). This paper identifies a population of DETCs that can produce large amounts of IL-17A in response to tissue injury and finds that DETC-derived IL-17A confers antimicrobial protection by inducing AMP production by keratinocytes.
Nielsen, M. M. et al. IL-1beta-dependent activation of dendritic epidermal T cells in contact hypersensitivity. J. Immunol. 192, 2975–2983 (2014).
Cai, Y. et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 35, 596–610 (2011).
O'Brien, R. L. & Born, W. K. Dermal gammadelta T cells—What have we learned? Cell. Immunol. 296, 62–69 (2015).
Nakatsuji, T. et al. The microbiome extends to subepidermal compartments of normal skin. Nat. Commun. 4, 1431 (2013).
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).
Leclercq, G. & Plum, J. Stimulation of TCR V gamma 3 cells by gram-negative bacteria. J. Immunol. 154, 5313–5319 (1995).
Nixon-Fulton, J. L. et al. Phenotypic heterogeneity and cytotoxic activity of Con A and IL-2-stimulated cultures of mouse Thy-1+ epidermal cells. J. Invest. Dermatol. 91, 62–68 (1988).
Takashima, A., Nixon-Fulton, J. L., Bergstresser, P. R. & Tigelaar, R. E. Thy-1+ dendritic epidermal cells in mice: precursor frequency analysis and cloning of concanavalin A-reactive cells. J. Invest. Dermatol. 90, 671–678 (1988).
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).
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).
Zhang, M. et al. Oral antibiotic treatment induces skin microbiota dysbiosis and influences wound healing. Microb. Ecol. 69, 415–421 (2015). This paper finds that orally treating mice with antibiotics leads to delayed wound healing and increased scarring, which is attributed to a shift in the dominant bacterial phyla and correlates with decreased IL-17A and REG3γ levels in wounded skin.
Canesso, M. C. et al. Skin wound healing is accelerated and scarless in the absence of commensal microbiota. J. Immunol. 193, 5171–5180 (2014). This paper shows that germ-free mice exhibit faster wound healing than conventionally housed mice and no scarring, indicating that the microbiota has a negative impact on wound healing kinetics and scarring.
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).
We thank the following funding sources: US National Institutes of Health (NIH) grants AI036964, AI1064811 and AI129401; The Danish Council for Independent Research 4183-00308B; and Lundbeckfonden R182-2014-3467.
The authors declare no competing financial interests.
- Butyrophilin-like (BTNL) molecules
Part of the B7 family of accessory molecules. They have immune-modulatory functions in both humans and mice. Although the precise mechanism remains unknown, the specific expression of individual BTNL family members in epithelial tissues selectively shapes and expands epithelial-specific γδ T cell repertoires.
- Langerhans cells
Dendritic cells that inhabit the epidermis. They are best distinguished by their high expression levels of the C-type lectin receptor langerin (also known as CD207) and its associated Birbeck granules. In contrast to other dendritic cells, Langerhans cells self-renew locally and are not depleted by high doses of X-ray irradiation.
- Innate lymphoid cells
(ILCs). A group of innate immune cells that are lymphoid in morphology and developmental origin but lack properties of adaptive B cells and T cells such as recombined antigen-specific receptors. They function in the regulation of immunity, tissue homeostasis and inflammation in response to cytokine stimulation.
Tubular invaginations of the intestinal epithelium. Lining the base of the crypts are small-intestinal Paneth cells, which produce numerous antimicrobial proteins, and stem cells, which continuously divide to give rise to the entire intestinal epithelium.
Finger-like protrusions into the intestinal lumen that create the vast surface area of the gastrointestinal tract. Their outer layer mainly consists of mature and absorptive enterocytes as well as some mucus-secreting goblet cells.
- Aryl hydrocarbon receptor
(AHR). A cytosolic, ligand-dependent basic helix–loop–helix transcription factor that translocates to the nucleus following the binding of specific ligands, which include dietary and microbial metabolites. AHR participates in the differentiation of several T cell subsets, such as regulatory T cells, T helper 17 cells and intraepithelial intestinal γδ T cells.
About this article
Cite this article
Nielsen, M., Witherden, D. & Havran, W. γδ T cells in homeostasis and host defence of epithelial barrier tissues. Nat Rev Immunol 17, 733–745 (2017). https://doi.org/10.1038/nri.2017.101
This article is cited by
Single-cell RNA sequencing reveals the local cell landscape in mouse epididymal initial segment during aging
Immunity & Ageing (2023)
Nature Immunology (2023)
Nature Immunology (2023)
Vγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males
Nature Communications (2023)
Signal Transduction and Targeted Therapy (2023)