SUMMARY Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharide lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo, and conferred a T helper 1 (Th1) cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection and cancer.

Significance Natural regulatory T cells (nTregs) play important roles in preventing autoimmune diseases, but they may be unstable in the presence of inflammation. Here we report that all - trans RA (atRA) but not rapamycin prevents human nTregs from converting to Th1/Th17 cells and sustains their suppressive function in inflammatory environments. Adoptive transfer of nTregs pretreated with atRA enhances their suppressive effects on xenograft-vs. - host diseases. Moreover, we show that atRA suppresses IL-1 receptor upregulation, accelerates IL-6 receptor downregulation, and affects the epigenetic modifications in Foxp3 locus in nTregs following inflammatory stimulation. We suggest that nTregs primed with atRA may represent a novel treatment strategy to control established chronic immune-mediated diseases.

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