Ubiquitin activating enzyme uba6 regulates th1 and tc1 cell differentiation

Abstract

Ubiquitination is a crucial mechanism in regulating the immune response, setting the balance between immunity and tolerance. Here, we investigated the function of a poorly understood alternative branch of the ubiquitin‐activating E1 enzyme UBA6 in activating immune cells. UBA6 expression levels were elevated in T cells by toll‐like receptor agonists and anti‐CD3/28 antibody stimulation, but not in dendritic cells, macrophages, B cells, and natural killer cells. Additionally, we generated T cell‐specific UBA6‐deficient mice and found that UBA6‐deficient CD4 and CD8 T cells elevated the production of interferon‐gamma (IFN‐γ). Moreover, the transfer of UBA6‐deficient CD4 and CD8 T cells in RAG1‐ knockout mice exacerbated the development of multi‐organ inflammation compared with control CD4 and CD8 T cell transfer. In human peripheral blood CD4 and CD8 T cells, basal levels of UBA6 in lupus patients presented much lower than those in healthy controls. Moreover, the IFN‐γ production efficiency of CD4 and CD8 T cells was negatively correlated to UBA6 levels in patients with lupus. Finally, we found that the function of UBA6 was mediated by destabilization of IκBα degradation, thereby increas-ing NF‐κB p65 activation in the T cells. Our study identifies UBA6 as a critical regulator of IFN‐γ production in T cells by modulating the NF‐κB p65 activation pathway.