Mucosal surfaces, as a first barrier with the environment are especially susceptible to damage from both pathogens and physical trauma. Thus, these sites require tightly regulated repair programs to maintain barrier function in the face of such insults. Barrier sites are also enriched for unconventional lymphocytes, which lack rearranged antigen receptors or express only a limited range of such receptors, such as ILCs (Innate Lymphoid Cells), γδ T Cells and MAIT (Mucosal-Associated Invariant T Cells). Recent studies have uncovered critical roles for unconventional lymphocytes in regulating mucosal barrier function, and, in particular, have highlighted their important involvement in barrier repair. The production of growth factors such as amphiregulin by ILC2, and fibroblast growth factors by γδ T cells have been shown to promote tissue repair at multiple barrier sites. Additionally, MAIT cells have been shown to exhibit pro-repair phenotypes and demonstrate microbiota-dependent promotion of murine skin healing. In this review we will discuss how immune responses at mucosal sites are controlled by unconventional lymphocytes and the ways in which these cells promote tissue repair to maintain barrier integrity in the skin, gut and lungs.
Psoriasis is a common chronic inflammatory skin disease with no cure. It is driven by the IL-23/IL-17A axis and TH17 cells but, recently group 3 innate lymphoid cells (ILC3s) have also been implicated. However, the development, and factors regulating the activity of ILC3s remain incompletely understood. Immune regulatory pathways are particularly important at barrier sites such as the skin, gut and lung, which are exposed to environmental substances and microbes. CD200R1 is an immune regulatory cell surface receptor which inhibits proinflammatory cytokine production in myeloid cells. CD200R1 is also highly expressed on ILCs, where its function remains largely unexplored. We previously observed reduced CD200R1 signalling in psoriasis skin, suggesting that dysregulation may promote disease. Here we show that contrary to this, psoriasis models are less severe in CD200R1-deficient mice due to reduced IL-17 production. Here we uncover a key cell-intrinsic role for CD200R1 in promoting IL-23-driven IL-17A production by ILC3s, by promoting STAT3 activation. CD200R1 is expressed on ILC precursors and is particularly high on neonatal ILC3s, suggesting CD200R1 may function during ILC development. Therefore, CD200R1 is required on ILC3s, potentially during their development, to promote IL-23-stimulated STAT3 activation triggering optimal IL-17 production.
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