The intrinsic and extrinsic regulation of γδ-T17 cells through the IL-17-IL-17r axis during homeostasis (LYM2P.729)

Abstract

Abstract IL-17 producing γδ T cells (γδ-T17) are major players in promoting several autoimmune inflammatory diseases and cancers. However, γδ-T17 homeostatic regulation has not been fully understood. In naïve, adult IL-17r-/- and IL-17A-/-/F-/- mice we observed higher frequencies of total γδ T cells, predominantly γδ-T17, in the lung, spleen, gut, LN and skin but not in the thymus. We hypothesized that the IL-17-IL-17r axis regulates peripheral γδ-T17 homeostasis. Two different regulatory pathways were identified to be involved in this regulation: extrinsically through microbiota-host interaction and intrinsically through IL-17r-IL-7r signaling interaction. The extrinsic pathway was discovered in vitro using CFSE-labeled IL-17r-/- lymphocytes that had endogenous γδ-T17 proliferation dependent upon DCs, particular CD103+ DCs, and IL-1β. Using mice delivered from IL-17r-/- pregnant females treated either with lymphotoxin beta receptor-Ig to remove LNs or antibiotics (ampicillin, vancomycin, neomycin, and metronidazole) to deplete gut microbiota we found significantly decreased frequency of γδ-T17 in peripheral tissues. Also, intrinsically IL-17r-/- γδ-T17 expressed higher levels of RORγt that suppressed BTLA expression, which is a known inhibitor of IL-7-driven γδ-T17 proliferation. Taken together, our findings suggest that the IL-17-IL-17r axis regulates γδ-T17 via both intrinsic and extrinsic pathways.