Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair

Abstract

Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.

Skin microbiota–host interactions

“…For instance, some strains of S. epidermidis induce activation of S. epidermidis -specific IL-17 + CD8 + T cells that protect against cutaneous infections by inducing keratinocytes to produce AMPs, a phenomenon called heterologous protection 45 . In addition to their protective role, these commensal-specific T cells also promote wound repair 46 . Of interest, S. epidermidis can elicit T cell responses restricted to non-classical major histocompatibility complex (MHC) class I molecules 46 .…”

“…In addition to their protective role, these commensal-specific T cells also promote wound repair 46 . Of interest, S. epidermidis can elicit T cell responses restricted to non-classical major histocompatibility complex (MHC) class I molecules 46 . Thus, non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, may play an important role in promoting homeostatic immunity to the microbiota.…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…In addition to the divergent effector cytokines, regular pathogen-induced T RM s are different from commensal-specific T RM s in three major aspects: 1) Pathogen infection-induced skin T RM cells are largely restricted to the injured site while commensal-specific T RM s are scattered; 2) Pathogen infection-induced T RM s directly respond to infected epidermal cells to produce IFN-γ while IL-17 production from commensal-specific T RM cells requires CD11b + local DCs;58–60 and 3) the unique population of IL-17 producing CD8 + skin T RM cells differentiate from non-classical MHC-Ib-restricted CD8 + T cells and promote tissue repair. 59 …”

“…Importantly, IL-17 producing CD8 + T cells are present in both human and non-human primates. 59 In human skin, the presence or absence of CD49a expression can divide T RM s into IFN-γ or IL-17-Producing cells and associated with type 1 or type 17 effector T cell-related disease settings. 62 However, the molecular and cellular control of the type 17 effector program in CD8 + T cells or T RM cells remains unclear.…”

MAIT cells: the end of the beginning?

“…And designing experiments in both animal models and in humans to test these ideas is an important challenge, as these cells appear to be functionally distinct between some species. Another interesting question emerging is whether their role extends beyond that of “emergency” responses, to include more homeostatic functions linked to interactions with commensal bacteria at barrier sites . Addressing this alternative lifestyle for MAIT cells and related T‐cell subsets will need a different type of experimental approach and clinical study but could be equally important.…”