REGULATION OF T FOLLICULAR CELL DEVELOPMENT BY E3 UBIQUITIN LIGASE CBL-B IN SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract

Abstract T follicular helper cells (Tfh) are critical in providing help to B cells, and have been shown to be involved in the overproduction of pathogenic auto-Abs and tissue damage in lupus. Cbl-b, a RING finger E3 ubiquitin ligase, negatively regulates lymphocyte activation. In this study, we found that the expression of Cbl-b in CD4+ T cells from lpr mice on a C57BL/6 background (B6-lpr) was down-regulated. Introducing Cbl-b deficiency or Cbl-b C373A mutation into B6-lpr mice significantly exacerbated the onset of the disease in B6-lpr mice, which correlated with heightened serum auto-antibody titers, exaggerated Tfh, GC B cells, and plasma cells. These data indicate that Cbl-b negatively regulates lupus disease progression and Tfh development via its E3 ubiquitin ligase activity. In support of a critical role of Cbl-b in Tfh development, mice specifically deficient for Cbl-b in T cells also exhibited an increase in Tfh when they were immunized with OVA in CFA. Mechanistically, Cbl-b appeared to specifically bind to Bcl6, and target Bcl-6 for ubiquitination and degradation. In strong support of Cbl-b in exaggerated Tfh in lupus, we found that Tfh cells were increased in the peripheral blood of SLE patients. Furthermore, Cbl-b expression was significantly reduced in Tfh from patient with SLE. Therefore, our data indicate that Cbl-b suppresses Tfh development by targeting Bcl6, and that deregulated expression of Cbl-b may play a crucial in aberrant Tfh development, thus eliciting pathogenic auto-Ab production by B cells.