Effector CD4 T cells with stem cell-like properties mediate chronic intestinal inflammation

Abstract

Abstract Increased IFNγ production is a hallmark of mucosal CD4 T cells in inflammatory bowel disease (IBD) patients; however, the role of this cell population in intestinal inflammation remains controversial. To elucidate this, viable IFNγ producing and non-producing CD4 T cells were isolated from mice with colitis and examined for the ability to confer disease. Paradoxical to the proinflammatory nature of IFNγ, CD4 T cells producing IFNγ cause attenuated pathology upon transfer, while IFNγ non-producing cells result in severe intestinal inflammation. The pathogenic IFNγ non-producing cells exhibit a “stem cell-like” gene expression pattern, maintaining genes associated with multipotency including Sell, Tcf7, Lef1, Klf2, and Wnt10a. Consistent with the “stem cell-like” gene signature, IFNγ non-producing CD4 T cells show higher cell survival, superior mitochondrial function, as well as functional plasticity. Conversely, IFNγ producing CD4 T cells express terminal differentiation markers, such as Klrg1, Tim3, Zeb2 and Prdm1, and are more susceptible to cell death. These divergent phenotypes correlate with the glycosyltransferase ST6Gal1. IFNγ nonproducing cells maintain higher levels of St6gal1 mRNA during colitis, while IFNγ producing cells downregulate St6gal1 gene expression. Furthermore, when IFNγ nonproducing cells lose ST6Gal1 activity, they become terminally differentiated, more susceptible to apoptosis and less pathogenic compared to IFNγ nonproducing cells with high ST6Gal1 activity. Together, these data indicate that effector CD4 T cells exist in a spectrum of differentiation states during IBD, from stem cell-like to terminally differentiated, which are associated with IFNγ production and ST6Gal1 activity.