Overexpression of T-bet in T cells accelerates autoimmune glomerulonephritis in mice with a dominant Th1 background

Background: An imbalance of T helper 1 (Th1)/Th2 is thought to contribute to the pathogenesis of autoimmune diseases. The differentiation of T cells into Th1 or Th2 subtypes is under the regulation of several transcription factors. Among these, transcription factor T-bet has been demonstrated to play an important role in Th1 cell differentiation. Methods: To examine how Th1/Th2 imbalance affects the development of autoimmune disease, we overexpressed T-bet in the T lymphocytes of C57BL/6 x BXSB/MpJ-Yaa F1 (Yaa) mice. Results: Yaa mice developed autoimmune nephritis similarly to BXSB/MpJ-Yaa mice, which are commonly used as a model for the Th1-dominant murine lupus. T-bet overexpression in T cells aggravated the 50% mortality of T-bet transgenic Yaa mice relative to Yaa mice, and increased proteinuria, the severity of glomerulonephritis in T-bet transgenic Yaa mice. T-bet overexpression in Yaa mice led simultaneously to an elevated ratio of Th1/Th2 immunoglobulin (IgG2a/IgG1). Intracellular cytokine analysis showed that IL-4 and IL-5 was suppressed, and IFN-gamma was induced in stimulated T cells from the T-bet transgenic Yaa mice. Conclusions: These results indicate that T-bet stimulated the differentiation of Th1 cells and accelerated the disease severity in Yaa mice. These results suggest that Th1/Th2 imbalance contributes to the glomerulonephritis severity in Yaa mice, and Th1/Th2 transcriptional regulation is important for autoimmune glomerulonephritis.