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Heat shocks T cells down a path to disease

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Science Immunology  06 Mar 2020:
Vol. 5, Issue 45, eabb4933
DOI: 10.1126/sciimmunol.abb4933

Abstract

Febrile temperatures enhance differentiation of CD4+ T cells into pathogenic TH17 cells that contribute to autoimmune disease.

Fever is a fundamental aspect of many infectious and inflammatory diseases, with various studies suggesting that fever enhances immune system functions in different ways. However, little is known about the effects of fever on T cell responses. Recently, Wang et al. discovered that febrile temperatures enhance cytokine-driven differentiation of pathogenic TH17 cells. They cultured naïve T cells under different TH subset polarizing conditions and demonstrated that TH17, but not TH1, TH2, or Treg, differentiation was significantly enhanced at 39.5°C compared to 37°C. Up-regulation of heat shock protein (HSP) 70 appeared to be necessary but not sufficient for the temperature-dependent response. They showed that unlike at 37°C, TH17 differentiation at 39.5°C was dependent on TGF-β1– and HSP- induced SUMOylation and nuclear translocation of SMAD4. RNA-seq pathway analysis comparing TH17 cells generated at 37°C versus 39.5°C revealed that top heat–up-regulated genes included those encoding TH17 cytokines (Il17, Il17f, and Il22) and receptors of cytokines that drive TH17 differentiation (Il1r1, l1r2, and Il23r). Also up-regulated were the genes previously associated with pathogenic TH17 cells in the CNS of mice with experimental autoimmune encephalitis (EAE) but not with nonpathogenic gut TH17 cells. The authors performed in vivo experiments that supported a role of fever in TH17 differentiation. The transfer of naïve Ova-specific TCR transgenic T cells into T cell–deficient mice, followed by adjuvant +Ova immunization, resulted in fever, induction of HSP genes, and TH17 differentiation, all of which were reduced by treatment of the mice with antipyretics. In a T cell adoptive transfer model of pulmonary disease, more inflammation was caused by TH17 cells generated at 39.5°C than 37°C. Using a MOG-specific (2D2) TCR-transgenic model of EAE with and without T cell SMAD4 deletion, the authors showed that T cell SMAD4 deficiency delayed onset and reduced severity of the CNS disease. Furthermore, the transferring of Smad4−/− 2D2 T cells infected with retrovirus expressing SUMOylation site mutant SMAD4 developed less severe diseases with fewer CNS TH17 cells than the transfer of WT Smad4-transduced T cells. These elegant studies leave unanswered some questions about the biochemical mechanisms of SMAD4 activation and downstream gene expression but will undoubtedly stimulate investigation of targeting this febrile pathway of pathogenic TH17 generation in autoimmune disease.

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