Abstract
T-bet is a key transcription factor for the T helper 1 lineage and its expression level is negatively correlated to inflammation in patients with rheumatoid arthritis (RA). Our previous study using T-bet transgenic mice revealed over-expression of T-bet completely suppressed collagen-induced arthritis (CIA), a murine model of RA, indicating a potential suppressive role of T-bet in the pathogenesis of autoimmune arthritis. Here, we show T-bet-deficiency exacerbated CIA. T-bet in CD4 + T cells, but not in CD11c + dendritic cells, was critical for regulating the production of IL-17A, IL-17F, IL-22, and TNFα from CD4 + T cells. T-bet-deficient CD4 + T cells showed higher RORγt expression and increased IL-17A production in RORγt-positive cells after CII immunization. In addition, T-bet-deficient naïve CD4 + T cells showed accelerated Th17 differentiation in vitro. CIA induced in CD4-Cre T-betfl/fl (cKO) mice was more severe and T-bet-deficient CD4 + T cells in the arthritic joints of cKO mice showed higher RORγt expression and increased IL-17A production. Transcriptome analysis of T-bet-deficient CD4 + T cells revealed that expression levels of Th17-related genes were selectively increased. Our results indicate that T-bet in CD4 + T cells repressed RORγt expression and function resulting in suppression of arthritogenic Th17 cells and CIA.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease characteristic of polyarthritis and, if uncontrolled, the subsequent joint destruction leads to impaired quality of life
We previously reported that T-bet transgenic (T-bet Tg) mice were resistant to Collagen-induced arthritis (CIA) with a reduction of rorc and ahr expression levels of CD4 + T cells leading to impaired collagen type II (CII)-reactive IL-17A production from CD4 + T cells[9,10]
Our findings indicate that T-bet in CD4 + T cells negatively regulates autoimmune arthritis by selective inhibition of T helper 17 (Th17) differentiation through suppression of RORγt expression and function resulting in inhibition of arthritogenic Th17 cells
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease characteristic of polyarthritis and, if uncontrolled, the subsequent joint destruction leads to impaired quality of life. The precise mechanism of RA remains elusive, CD4 + T cells, especially their subsets and the transcriptional regulation of their differentiation into specific subsets, seem to play a critical role in the pathogenesis of autoimmune arthritis. We previously reported that T-bet transgenic (T-bet Tg) mice were resistant to CIA with a reduction of rorc and ahr expression levels of CD4 + T cells leading to impaired CII-reactive IL-17A production from CD4 + T cells[9,10]. The precise role of T-bet in the pathogenesis of CIA from the perspective of lineage commitment of CD4 + T cells remains to be elucidated. Our findings indicate that T-bet in CD4 + T cells negatively regulates autoimmune arthritis by selective inhibition of Th17 differentiation through suppression of RORγt expression and function resulting in inhibition of arthritogenic Th17 cells
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