Innate CD8αα cells orchestrate intraepithelial lymphocytes balance and protect against colitis

Abstract

Abstract Innate CD8αα+ cells (iCD8α) are TCRneg intraepithelial lymphocytes (IEL) that possess immune functions such as phagocytosis, bacteria killing, and antigen processing and presentation. Recently our group and others reported that iCD8α cells promote IEL survival via osteopontin. Herein, we investigate whether iCD8α cells sustain intestinal homeostasis through maintaining IEL balance. We compared the number of IEL in the colon of WT and iCD8α-deficient mice (E8i−/−). E8i is an enhancer required for CD8α homodimer expression in IEL. Despite the dramatic reduction of CD8αα expression on TCRαβ+ and TCRgd+ IEL in E8i−/− mice, the total cell numbers were comparable to WT mice. E8i−/− mice had higher number of TCRβ+CD4+, and lower number of TCRβ+CD4+CD8α+ and TCRβ+CD8αα+ IEL. There were no differences in TCRβ+CD8αβ+ and TCRneg IEL. Then, we tested the role of iCD8α cells during intestinal inflammation in different colitis models. iCD8α-deficient mice had higher susceptibility to Citrobacter rodentium infection as indicated by increased weight loss, disease index, and bacterial load in the colon compared to WT mice. Similar results were obtained using DSS-induced colitis: E8i−/− mice presented increased shortening of colon and pathological scores. Finally, we performed adoptive transfer of naïve CD4 T cells into Rag-2−/− and E8i−/−Rag-2−/− mice. iCD8α-deficient mice rapidly developed chronic colitis, manifested by sever weight loss and bloody diarrhea. These mice also reconstituted with higher number of donor-derived CD4 T cells that mostly developed into pathogenic TCRβ+CD4+ IEL. Our results indicate that iCD8α cells have a critical role in the maintenance of IEL homeostasis and healthy intestines.