Innate γδT17 cells play a protective role in DSS-induced colitis via recruitment of Gr-1⁺CD11b⁺ myeloid suppressor cells

Abstract

Innate γδ T cells play critical roles in mucosal immunity such as regulating intestinal epithelial homeostasis. In addition, γδ T cells are significantly increased in the inflamed mucosa of patients with ulcerative colitis. However, γδ T cells are a heterogeneous population. IL-17-producing versus IFNγ-producing γδ T cells play differential roles in different disease settings. Therefore, dissecting the exact role of different subsets of γδ T cells in colitis is essential for understanding colitis immunopathogenesis. In the current study, we found that TCR δ-deficient mice had a more severe dextran sodium sulfate (DSS)-induced colitis that was reduced upon reconstitution of γδT17 cells but not IFNγ-producing γδ T cells. Immunophenotyping of the cellular infiltrate upon DSS-induced colitis showed a reduced infiltration of Gr-1CD11b myeloid cells into the sites of inflammation in mice lacking γδT17 cells. Further experiments demonstrated that IL-17, IL-18, and chemokine CXCL5 were critical in Gr-1CD11b myeloid cell recruitment. T cell suppressive assay indicated that this Gr-1CD11b population was immunosuppressive. Depletion of Gr-1CD11b myeloid cells resulted in an increase severity of DSS-induced colitis. Our study elucidates a new immune pathway involving γδT17-dependent recruitment of Gr-1CD11b myeloid cells to the site of colitis inflammation important in the protection of colitis initiation and progression.

IL-17A-producing γδ T cells promote liver pathology in acute murine schistosomiasis

“…Vγ2 cells, whose most striking feature is the secretion of IL-17A, are involved in immune responses and various diseases. They not only play protective roles against colitis and viruses, but also promote liver fibrosis [16,48], especially, γδ T cells could exacerbate liver fibrosis by aiding the activation of HSCs in liver fibrosis induced by carbon tetrachloride injection [49]. Our observations show that during infection, the increase in Vγ2 cells was accompanied by an increase in their secreted IL-17A.…”

“…As a member of the IL-17 family, IL-17A is involved in various biological processes by binding its cognate receptor, IL-17RA [10][11][12][13]. Accumulating evidence demonstrates that IL-17A is related to a variety of inflammatory and autoimmune diseases such as inflammatory bowel diseases (IBD) and multiple sclerosis [14][15][16]. Multiple studies have demonstrated that Th17 cells, natural killer T cells and γδ T cells produce IL-17A [17][18][19].…”

γδ T Cells: Crosstalk Between Microbiota, Chronic Inflammation, and Colorectal Cancer

“…Secretion of IL-17 could activate Act-1 (a key adaptor protein of IL-17 receptor), which attenuated inflammation and immobilized the localization of occluding (a tight junction protein) to prevent excessive intestinal permeability (Figure 2 ) ( 68 ). Another crucial anti-inflammatory pathway of γδ T cells is linked to the recruitment of MDSCs ( 29 ). Sun et al observed that TCRγδ-deficient mice were more susceptible to dextran sulfate sodium-induced colitis, with a reduced expression of IL-18 and CXCL5 relative to wild-type mice, which was important for the subsequent Gr-1 + CD11b + suppressor cell infiltration ( 29 ).…”

“…Another crucial anti-inflammatory pathway of γδ T cells is linked to the recruitment of MDSCs ( 29 ). Sun et al observed that TCRγδ-deficient mice were more susceptible to dextran sulfate sodium-induced colitis, with a reduced expression of IL-18 and CXCL5 relative to wild-type mice, which was important for the subsequent Gr-1 + CD11b + suppressor cell infiltration ( 29 ). Moreover, mice reconstituted with γδT17 cells (mainly Vγ6) had ameliorated intestinal inflammation and were associated with increased frequency of Gr-1 + CD11b + cells, whereas mice with IFN-γ producing γδ T cells had no significant difference, indicating a protective role of γδT17 cells (but not IFN-γ producing γδ T cells) to a certain extent ( 29 ).…”

“…During microbial dysbiosis, resident Vδ1 + T cells are indispensable for triggering early protective inflammatory responses, which are essential for wound healing ( 22 , 24 , 26 ). Once the inflammatory response persists, Vδ1 + T cells subtly provide the foundation for angiogenesis, survival signal pathway activation, and myeloid-derived suppressor cell (MDSC) recruitment, thereby generating a chronic pre-cancerous inflammatory environment ( 27 – 29 ). In such cancer or stressed cells, isopentenyl pyrophosphate (IPP) gradually accumulates and boosts the activation of Vγ9Vδ2 T cells, which only take up a small fraction of lymphocytes in peripheral blood (PB), but harbor an antineoplastic effect ( 30 , 31 ).…”