Epithelial surfaces line the body and provide a critical interface between the body and the external environment which is essential to maintaining the symbiotic relationship between the host and the microbiome. Tissue-resident epithelial γδ T cells represent a major T cell population in epithelia and are ideally positioned to perform barrier surveillance and aid in tissue homeostasis and repair. In this review we focus on the intraepithelial γδ compartment in the two largest epithelial tissues in the body, namely the epidermis and intestine, and provide a comprehensive overview of the crucial contributions of intraepithelial γδ cells at these sites to tissue integrity and repair, host homeostasis and host protection in the context of the symbiotic relationship with the microbiome and during pathogen clearance. Finally, we address epithelia-specific butyrophilin-like molecules and touch upon their emerging role in selectively shaping and regulating epidermal and intestinal γδ T cell repertoires.

SummaryBackground. Skin-resident memory T (T RM ) cells are associated with immunological memory in the skin. Whether immunological memory responses to allergens in the skin are solely localized to previously allergen-exposed sites or are present globally in the skin is not clear. Furthermore, the mechanisms whereby T RM cells induce rapid recall responses need further investigation. Objectives. To study whether contact allergens induce local and/or global memory, and to determine the mechanisms involved in memory responses in the skin. Methods. To address these questions, we analysed responses to contact allergens in mice and humans sensitized to 2,4-dinitrofluorobenzene and nickel, respectively. Results. Challenge responses in both mice and humans were dramatically increased at sites previously exposed to allergens as compared with previously unexposed sites. Importantly, the magnitude of the challenge response correlated with the epidermal accumulation of interleukin (IL)-17A-producing and interferon (IFN)--producing T RM cells. Moreover, IL-17A and IFN-enhanced allergen-induced IL-1 production in keratinocytes. Conclusions. We show that sensitization with contact allergens induces a strong, longlasting local memory and a weaker, temporary global immunological memory response to the allergen that is mediated by IL-17A-producing and IFN--producing CD8 + T RM cells.

Substances that penetrate the skin surface can act as allergens and induce a T cell-mediated inflammatory skin disease called contact hypersensitivity (CHS). IL-17 is a key cytokine in CHS and was originally thought to be produced solely by CD4+ T cells. However, it is now known that several cell types including γδ T cells can produce IL-17. Here, we determine the role of γδ T cells, especially the dendritic epidermal T cells (DETC), in CHS. By use of a well-established model for CHS where dinitroflourobenzen (DNFB) is used as allergen, we found that γδ T cells are important players in CHS. Thus, an increased number of IL-17 producing DETC appear in the skin following exposure to DNFB in WT mice, and DNFB-induced ear-swelling is reduced by approximately 50% in TCRδ−/− mice compared to WT mice. In accordance, DNFB-induced ear-swelling was reduced by approximately 50% in IL-17−/− mice. We show that DNFB triggers DETC activation and IL-1β production in the skin, and that keratinocytes produce IL-1β when stimulated with DNFB. We find that DETC activated in vitro by incubation with anti-CD3 and IL-1β produce IL-17. Importantly, we demonstrate that the IL-1 receptor antagonist anakinra significantly reduces CHS responses as measured by decreased ear-swelling, inhibition of local DETC activation and a reduction in the number of IL-17+ γδ T cells and DETC in the draining lymph nodes. Taken together, we show that DETC become activated and produce IL-17 in an IL-1β-dependent manner during CHS suggesting a key role for DETC in CHS.

No abstract

Our findings suggest that mixtures of allergens increase the primary response that potentiates the generation of memory T cells in response to the specific allergen. Thus, allergen mixtures enhance both induction and elicitation of contact allergy.

Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme1–4. Here we show that despite tryptophan depletion, in-frame protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) as the major event facilitating this process, and pinpointed tryptophanyl-tRNA synthetase (WARS1) as its source. We call these W>F peptides ‘substitutants’ to distinguish them from genetically encoded mutants. Using large-scale proteomics analyses, we demonstrate W>F substitutants to be highly abundant in multiple cancer types. W>F substitutants were enriched in tumours relative to matching adjacent normal tissues, and were associated with increased IDO1 expression, oncogenic signalling and the tumour-immune microenvironment. Functionally, W>F substitutants can impair protein activity, but also expand the landscape of antigens presented at the cell surface to activate T cell responses. Thus, substitutants are generated by an alternative decoding mechanism with potential effects on gene function and tumour immunoreactivity.

The interaction between keratinocytes (KC) and skin-resident immune cells plays an important role in induction of contact hypersensitivity (CHS). A specific subset of γδ T cells termed dendritic epidermal T cells (DETC) are located in mouse epidermis, and we have recently shown that DETC become activated and produce IL-17 in an IL-1β-dependent manner during CHS. Various receptors on DETC, including NKG2D, are involved in DETC responses against tumors and during wound healing. The ligands for NKG2D (NKG2DL) are stress-induced proteins such as Mult-1, H60, Rae-1 in mice and MICA, MICB and ULBP in humans. Here, we show that allergens up-regulate expression of the NKG2DL Mult-1, H60 and Rae-1 in cultured mouse KC and of MICA in primary human KC. We demonstrate that Mult-1 is expressed in mouse skin exposed to allergen. Furthermore, we find that the vast majority of DETC in murine epidermis and skin-homing cutaneous lymphocyte-associated antigen (CLA) positive γδ T cells in humans express NKG2D. Finally, we demonstrate that blocking of NKG2D partially inhibits allergen-induced DETC activation. These findings demonstrate that NKG2D and NKG2DL are involved in allergen-induced activation of DETC and indicate that the NKG2D/NKG2DL pathway might be a potential target for treatment of CHS.

This new model for nickel allergy that reflects epicutaneous exposure to nickel in humans shows that nickel allergy is dependent on MyD88 and IL-1 receptor signalling, but independent of TLR4.