Cutting Edge: The Pathogenicity of IFN-γ–Producing Th17 Cells Is Independent of T-bet

Abstract

During the development of experimental autoimmune encephalomyelitis (EAE), the proportion of pathogenic and myelin-specific cells within CNS-infiltrating cytokine producing T helper (Th) cells is unknown. Using an IL-17A-IFN-γ double reporter mouse and I-Ab/MOG38–49 tetramer, we show here that IL-17+ IFN-γ+ Th cells, which are expanded in the CNS during EAE, are highly enriched in MOG-specific T cells. We further demonstrate that IL-23 is essential for the generation and expansion of IFN-γ producing Th17 cells independently of the Th1-associated transcription factors T-bet, STAT1 and STAT4. Furthermore, Th17 and IL-17+ IFN-γ+ Th cells can induce CNS autoimmunity independently of T-bet. While T-bet is crucial for Th1 mediated EAE T-bet is dispensable for Th17 cell-mediated autoimmunity. Our results suggest the existence of different epigenetic programs that regulate IFN-γ expression in Th1 and Th17 cells.

Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis

“…Interestingly, however, in each of these studies, a population of IL-17A + IFN-γ + T cells developed in the absence of T-bet expression by CD4 + T cells, consistent with findings herein. Whereas these dual positive cells appear to be nonpathogenic in the intestines, their presence was associated with disease in EAE in at least one study (31). These findings expose likely differences between pathogenesis in the intestines and CNS.…”

“…Interestingly, other studies suggest that T-bet expression by T cells is not absolutely required for EAE pathogenesis, although disease was blunted in its absence (31,32). This finding might reflect differences in the role of T-bet in the Th17 to Th1 transition of Th17 cells differentiated ex vivo versus those that differentiate in vivo, which warrants further study.…”

The role of human CD1c+ DCs at activating innate and adaptive immune responses

“…Stimulation of memory CD4 + T cells with IL-12p70 promotes memory CD4 + T cell proliferation and IFN-γ production (Oppmann et al, 2000). The role of IL-12p70 in promoting transition of memory Th17 cells towards Th1 phenotype was previously reported (Annunziato et al, 2007, Duhen et al, 2013. Duhen et al demonstrated that IL-12p70 in combination with IL-1β enhanced T-bet and STAT4 expression in memory Th17 cells, leading to production of IL-17A, IFN-γ and GM-CSF (Duhen et al, 2013).…”

“…induces IFN-γ IL-17A-double producing T cells and repression of IL-10 induction (Duhen et al, 2013, Ramesh et al, 2014 (Figure 1.2). Stimulation of memory CD4 + T cells with IL-12p70 promotes memory CD4 + T cell proliferation and IFN-γ production (Oppmann et al, 2000).…”

“…Memory Th cells are known to display functional plasticity and their ability to transition from one phenotype to the other is highly influenced by inflammatory stimuli. One such example would be the plasticity of memory Th17 cells towards Th1 phenotype which are now known as Th17.1 cells (Annunziato et al, 2007, Boniface et al, 2010, Cosmi et al, 2008, Duhen et al, 2013, Ramesh et al, 2014 (Figure 1.2).…”