Abstract
Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic and autoimmune diseases. To identify factors contributing to these response differences, here we analyze in vitro differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicates that the p53 family protein, p73, affects Th1 differentiation. In cells differentiated under Th1 conditions in vitro, p73 negatively regulates IFNγ production. p73 binds within, or upstream of, and modulates the expression of Th1 differentiation-related genes such as Ifng and Il12rb2. Furthermore, in mouse experimental autoimmune encephalitis, p73-deficient mice have increased IFNγ production and less disease severity, whereas in an adoptive transfer model of inflammatory bowel disease, transfer of p73-deficient naïve CD4+ T cells increases Th1 responses and augments disease severity. Our results thus identify p73 as a negative regulator of the Th1 immune response, suggesting that p73 dysregulation may contribute to susceptibility to autoimmune disease.
Highlights
Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic and autoimmune diseases
SM/J, 129S, and NZB splenocytes had relatively high Ifng mRNA expression compared to the other strains at most time points (Supplementary Fig. 1), with strong and significant inter-strain differences in Ifng mRNA expression (P values were
Trp[73] was not previously known to play a role in Th cell differentiation, but based on its important roles in the development and progression of cancer, we investigated whether this transcription factor plays a role in Th1 differentiation
Summary
Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic and autoimmune diseases. Our results identify p73 as a negative regulator of the Th1 immune response, suggesting that p73 dysregulation may contribute to susceptibility to autoimmune disease. To further identify the factor(s) involved, we used haplotype-based computational genetic mapping (HBCGM)[5,6] to analyze Th1 differentiation data from multiple mouse strains. From this analysis, we identified a p53 family member, Transformation related protein 73 gene (Trp73)[7], as a regulator of Th1 differentiation. In experimental allergic encephalitis, a mouse model of multiple sclerosis (MS), we find augmented IFNγ expression by cells from Trp73−/− mice and show that these animals have decreased disease severity, whereas in a model of adoptive transfer inflammatory bowel disease, Rag2−/− hosts receiving of p73-deficient naive CD4+ T cells as opposed to wild-type (WT) T cells have augmented Th1 responses as well as greater disease
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