Pathogenicity of IFN-γ+ Th17 cells is independent of T-bet (P4128)

Abstract

Abstract It is now established that T helper (Th) cell subsets, particularly Th17 cells, are more dynamic than originally anticipated and can acquire the expression of other lineage effector cytokines. However, the molecular cues that dictate their plasticity are unknown. We show that IL-23 plays a central role in the plasticity of Th17 cells and is essential for the generation and propagation of IFN-γ-producing Th17 (IL-17+ IFN-γ+) cells. During the development of experimental autoimmune encephalomyelitis (EAE) IL-17+ IFN-γ+ T cells are preferentially expanded in the central nervous system (CNS). Using an IL-17A-IFN-γ double reporter mouse and I-Ab/MOG38-49 tetramer, we determined that they displayed characteristics of pathogenic T cells, such as GM-CSF expression, and contained the highest number of MOG-specific T cells. Interestingly, the Th1-associated transcription factors T-bet, STAT1 and STAT4 were not involved in the induction of IFN-γ by Th17 cells in vitro. Moreover, in contrast to previous studies showing a role for T-bet in Th1 and Th17-mediated EAE, we demonstrate that T-bet expression in T cells is not required for the emergence of CNS-infiltrating IL-17+ IFN-γ+ T cells and the development of Th17-driven EAE. Our results suggest the existence of different epigenetic programs that regulate IFN-γ expression in Th1 and Th17 cells.