Autoreactive Tbet-positive CD4 T cells develop independent of classic Th1 cytokine signaling during EAE (44.45)

Abstract Many autoimmune diseases are associated with the presence of Th1 and Th17 effector CD4 T cells. Paradoxically, the principal Th1 cytokine IFNγ does not appear necessary for disease, but the key Th1-associated transcription factor Tbet is required. This conundrum propelled us to investigate the regulation of this transcription factor during autoimmunity. Following the onset of experimental autoimmune encephalomyelitis (EAE), we observed a preferential upregulation of Tbet by CD4 T cells within the CNS, but not the secondary lymphoid organs. These Tbet-positive CD4 T cells were capable of producing the cytokine IFNγ, and a proportion of these cells produced both IFNγ and IL-17A. Interestingly, these Tbet-positive cells were present in high frequencies during disease in IFNγ-deficient mice. Moreover, we found that CD4 T cells from IFNγ-deficient/IFNγ reporter mice upregulated the Thy1.1 reporter, indicating the presence of Th1 or “Th1-like”, Tbet-positive CD4 T cells even in the absence of the cardinal Th1 cytokine, IFNγ. These data support the concept that Th1 cells contribute to EAE in a Tbet-dependent, IFNγ-independent manner. We further examined the requirement of other Th1-associated molecules in controlling Tbet expression during EAE, and noted that STAT1, IL-12, and IFNγ were dispensable for the induction of Tbet in vivo. Hence, this study highlights the complex regulation of Tbet and the potential unrecognized role for Th1 cells during autoimmunity.