Functional role of T-bet-dependent Th17 to Th1 cell plasticity in immune-mediated diseases

Abstract

T cells play an important role in the defense against various pathogens. They are also involved in the development of autoimmune mediated diseases. Th1 and Th17 cells are particularly prevalent in this regard. Th17 cells have been linked to pathogenicity mainly via expression of the name giving cytokines IL-17A and IL-17F. Depending on the cytokine environment, Th17 cells can transdifferentiate towards other T helper subsets. These include Tregs, Tfh and Th1 cells. Plasticity towards Th1 cells involves the Th17 subpopulations Th1-like and exTh17 cells. These subsets have been linked to pathogenicity in experimental autoimmune encephalomyelitis and intestinal bowel disease. In crescentic glomerulonephritis, Th17 cells have been shown to be very stable. Despite an increasing focus, the drivers of pathogenicity of the Th17-Th1 subpopulations remain incompletely understood. T-bet as the master TF of the Th1 lineage is crucial for the transdifferentiation of Th17 cells towards Th1 cells. Using a Th17 specific knockout of T-bet, we aimed to better understand the role of the Th17-Th1 axis in pathogenicity in crescentic glomerulonephritis and intestinal bowel disease. The experiments conducted show that the expression of T-bet in Th17 cells actively drives pathogenicity in CD45RBhi colitis, while it is dispensable for pathogenicity in crescentic glomerulonephritis. Reduced pathogenicity is most likely conditioned by the direct implication of T-bet in the expression of IFN-g in Th17 cells. In line with previous data, we saw a downsized exTh17 and enlarged Th1-like and bona fide Th17 populations following the Th17 specific T-bet knockout. T-bet might act as a checkpoint gene in transition of Th1-like to exTh17 cells via suppression of IL-17A expression in Th1-like cells. IFN-g expression in Th1-like cells was independent of T-bet and could play an important role in the development of Crohn’s disease. Further research on the TFs that drive the formation of Th1-like Th17 cells in Crohn’s disease is needed. A decreased exTh17 and enlarged Th1-like population in IL17ACRE x Tbx21flox CD45RBhi colitis animals did result in less severe weight loss. ExTh17 cells therefore appear to be more potent inducers of wasting disease than Th1-like cells. In addition, T-bet is involved in regulating the migratory capacity of cells of the Th17-Th1 axis via induction of CXCR3 and inhibition of CCR6.