Atg7 in CD4+ T cells improves intestinal mucosal inflammation by regulating Ets1‐mediated T cell differentiation

Atg7-autophagy-related gene 7 contributes as an immune cell function regulator, particularly involved in CD4⁺ T cell response. Nevertheless, the specific contribution of Atg7 in CD4⁺ T cells sensitive immune responses in inflammatory bowel disease (IBD) remains largely unclear. This study explores the functional significance and regulatory mechanisms of CD4⁺ T cell-specific Atg7 in IBD. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), western blotting analysis, flow cytometry and immunohistochemistry were employed to evaluate ATG7 expression in peripheral blood and colonic mucosal biopsies from IBD patients. Peripheral CD4⁺ T cells were transfected with lentivirus vectors encoding either ATG7 (LV-ATG7) or ATG7 short hairpin RNA (LV-shATG7). Furthermore, mice with a CD4⁺ T cell conditional knockout of Atg7 (Atg7ΔCD4) were generated, and CD4+ T cells of splenic origin were subjected to RNA-seq. ATG7 level was markedly elevated in inflamed mucosa tissues and peripheral blood CD4+ T cells of patients with active Crohn's disease compared to healthy individuals. Overexpression of ATG7 suppressed Th1 differentiation while enhancing the induction of iTreg cells. Atg7ΔCD4 mice exhibited exacerbated result of 2,4,6-trinitrobenzenesulphonic acid-induced experimental colitis, as did Rag1-/- mice adoptively transferred with CD45RBhigh CD4+ T cells from Atg7ΔCD4 donors. RNA-seq analysis revealed that E26 transformation-specific sequence-1 (Ets1) acts downstream of Atg7 and mediates its regulatory effects on Th1 and Treg cell differentiation. Our data indicate that Atg7 alleviates mucosal inflammation by modulating Th1/Treg differentiation through the regulation of Ets1 expression. Thus, CD4⁺ T cell-expressed Atg7 may serve as a promising therapeutic approach for IBD. Atg7 expression was significantly elevated in the inflamed mucosa and blood CD4+ T cells of patients with active Crohn's disease. Specific-knockout of Atg7 in CD4+ T cells leads to exacerbated colitis severity. Ets1 functions as a target of Atg7, where it inhibits Th1 cell differentiation and promotes Treg cell differentiation.