Figure 5

T follicular helper (Tfh) cells are CD4+ T cells specialized in providing help to B cells, particularly within germinal centers, which are distinct structures in secondary lymphoid organs. Appropriate activation of Tfh cells is essential for germinal center formation, affinity maturation, and the development of most high-affinity antibodies and memory B cells which are crucial for protective immune responses. However, aberrant activation of Tfh cells may contribute to the development of antibody-mediated autoimmunity such as systemic lupus erythematosus (SLE). The regulation of Tfh cell development is largely unknown. Cbl-b is a RING finger E3 ubiquitin ligase and intracellular adaptor protein that plays a key role in the negative regulation of lymphocyte function. Previously, we reported that loss of Cbl-b elicits heightened T-dependent antibody responses and germinal center formation, and that introduction of the CD40 deficiency into Cblb−/− mice significantly abrogated these responses. These findings suggest that Cbl-b modulates humoral immune responses through its interaction with the CD40-dependent pathway, and that the augmentation of Tfh responses may play a role in this process. Indeed, we found that the activity of Tfh cells is heightened in mice lacking Cbl-b upon immunization and influenza A viral infection. Furthermore, introducing Cbl-b deficiency into C57BL/6 lpr (B6-lpr.Cblb–/–) mice significantly exacerbates lupus disease progression. Further analysis indicates that Cbl-b deficiency in B6-lpr mice exaggerates the CD4+CXCR5+Bcl6+ Tfh population. At the molecular level, Cbl-b binds to Bcl6 upon TCR/CD28 stimulation, and loss of Cbl-b stabilizes Bcl-6 protein. These data suggest that Cbl-b is a potential E3 ubiquitin ligase for Bcl6. Based upon these data, we hypothesize that Cbl-b regulates Tfh cell development by targeting Bcl6 for polyubiquitination, thus controlling Tfh-mediated immune responses against viral infection, and possibly the development of lupus. To test this hypothesis, we will determine 1) whether Cbl-b inhibits Tfh cell development, thus dampening anti-viral humoral response but attenuating lupus disease; and 2) how Cbl-b controls Tfh cell development. Understanding the regulation of Tfh cell differentiation and function is of central importance for anti-viral immune responses, and the pathogenesis of systemic autoimmunity such as SLE.  Manipulating Cbl-b expression may represent potential therapeutic approaches for anti-viral immunity and certain autoimmune diseases including SLE.