Differential metabolic features and pathogenic potential of effector CD4 T cells associated with IFNγ production during intestinal inflammation (MUC5P.749)

Abstract

Abstract Interferon γ (IFNγ) production is a hallmark feature of mucosal CD4 T cells in inflammatory bowel disease (IBD) patients and multiple mouse models of colitis. However, the contribution of the IFNγ producing cell population to chronic intestinal inflammation remains controversial and requires better understanding. Recent studies have linked cellular metabolism to effector functions of immune cells, but it is unknown if discrete effector T cell subsets present during IBD possess divergent metabolic properties and differential T cell pathogenicity. Using IFNγ reporter mice, viable IFNγ secreting and non-secreting CD4 T cells were isolated from mice with active colitis and examined for metabolic characteristics. While both IFNγ producing and non-producing cells exhibit a high rate of glycolysis, interestingly, the mitochondrial function differs; IFNγ producing cells have lower oxidative phosphorylation and blunted spare respiratory capacity, indicating defective mitochondrial function compared to IFNγ non-producing cells. Consistent with decreased mitochondrial function, IFNγ producing cells have lower cell recovery upon secondary transfer and result in more attenuated intestinal inflammation. Therefore, these data suggest that CD4 T cells that upregulate IFNγ mark a unique effector cell subset with distinctive metabolic features, impaired survival, and reduced pathogenicity, which is paradoxical to the proinflammatory nature of IFNγ during chronic intestinal inflammation.