Maintenance of Barrier Tissue Integrity by Unconventional Lymphocytes

Abstract

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.

Mucosal-associated invariant T cells for cancer immunotherapy

“… 41 , 80 , 81 , 82 Previous studies have summarized the latest advances in dissecting the developmental trajectories and specific environmental cues that might skew MAIT cells toward tissue-repair-related phenotypes within both human and murine models. 83 , 84 In human, TCR-dependent activation induced enrichment of tissue-repair-associated type-17 MAIT cells, while TCR-independent activation mainly promoted antimicrobial inflammatory type-1 MAIT cells, secreting IFN-γ and TNF-α. 82 Although there is a paucity of murine MAIT cells present in peripheral blood, Constantinides et al.…”

“…This might be partially explained by the issue that current functional studies and transcriptional analysis of type-17 MAIT cells have failed to elucidate the exact molecular mechanism by which type-17 MAIT cells contribute to tissue repair. 84 It is conceivable to postulate that the seemingly immunosuppressive phenotype of type-17 MAIT cells might play a protumor role in the solid tumor microenvironment, and previous evidence has shown that the closely related type-17 γδ T cells contribute to tumor growth and metastasis in human cancer by secretion of IL-17A, IL-8, and GM-CSF, which in turn recruit myeloid-derived suppressor cells (MDSCs). 85 However, whether type-17 MAIT cells are indeed immunosuppressive and protumor or if a similar cellular crosstalk exists between MDSCs and type-17 MAIT cells has yet to be determined.…”

The Role of Gut Dysbiosis in the Loss of Intestinal Immune Cell Functions and Viral Pathogenesis

“…The organisms constituting the gut microbiota are typically separated from the host by the mucosal epithelium, which is composed of a single layer of tightly connected intestinal epithelial cells (IECs) and functions as a physical and chemical barrier [ 44 ]. IECs express receptors for the cytokines IL-17 and IL-22 produced by specialized tissue-resident lymphocytes including CD4 T, CD8 T, and innate lymphoid cells [ 45 , 46 ]. The dysregulation of IL-17/IL-22 cytokine secretion could lead to intestinal barrier disruption and the development of age-related inflammation [ 15 ], which is a likely factor underlying worse outcomes of viral infections in aging individuals.…”

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

“…MAIT cells can be viewed as “emergency responders” to invasion of mucocutaneous surfaces ( Shaler et al., 2017 ) as they are capable of producing pro- and/or anti-inflammatory cytokines (e.g., IFN-γ, TNF-α, IL-4, IL-10) readily after invariant T cell receptor (iTCR) stimulation. MAIT cells are an important source for IL-17 production in the mucosa and play a protective role in bacterial pneumonia ( Hannaway et al., 2020 ) and skin infections ( Cox et al., 2021 ). MAIT cells are much more predominant in human skin and mucosa than in mice.…”