IL-17-producing CD8+ T cells differ in phenotype, metabolic profile and cytokine production to their CD4+ Th17 counterparts

Th17 cells (CD4+ T cells producing IL-17) are important for clearance of fungal infections and play a critical role in the development and exacerbation of numerous autoimmune diseases. Their differentiation, signalling pathways, cytokine production and metabolism are now well-characterised. As well as CD4+ T cells, CD8+ cells also produce IL-17 family members, and these have been named Tc17 cells. However, much less is known about their development, signalling or metabolism compared to their CD4+ counterparts. Here, we performed a series of in vitro and in vivo analyses of Tc17 cells as well as computational analysis of the published Tabula muris dataset, comparing Tc17 to IL-17- CD8+ T cells and to Th17 cells. We show that murine Tc17 cells are generated in the presence of TGF-{beta} and IL-6, and that cells produced by these culture conditions substantially reflect Tc17 cells seen in vivo; that is, with high expression of PD1, CD6, ICOS and CD161. Tc17 cells show phenotypic and functional differences to their Th17 counterparts, with increased production of IL-2 and IL-22 as well as an increased tendency to produce IL-17F as well as IL-17A. They show a more glycolytic profile than Th17 cells, with lowered mitochondrial membrane potential. This divergent phenotype and cytokine production suggests differential roles in vivo for these two cells.