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.
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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.
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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
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