The deficiency of Cbl family in human elicits heightened T-dependent immune activation with augmentation of T-FH responses

Abstract T follicular helper (TFH) cells are functional subset CD4+ T cells in providing help to B cells and aberrant expansion of TFH cells is observed in systemic lupus erythematosus (SLE), which suggests a global defect in the maintenance of T and B cell tolerance. The mechanisms underlying uncontrolled TFH cells development and differentiation in SLE pathogenesis is fragmentary understand. Casitas B-lineage lymphoma (Cbl) family is an E3 ubiquitin ligase and has been implicated in SLE pathogenesis as a potent regulator in activating the immune cells and maintaining peripheral tolerance. The deficiency of cbl-b mice spontaneously develops autoimmunity and is highly susceptible to develop pathogenic auto-antibodies of autoimmune diseases. Through CRISPR KO system, we identified the deficiency of cbl/cbl-b in human naïve CD4+ T cells induces the TFH expansion in T cell stimulation with Activin A & IL12. Indeed, higher levels of chemokine (C-X-C motif) ligand 13 (CXCL13) which is constitutively produced in germinal center (GC) TFH cells were detected. Functionally, cbl/cbl-b KO TFH cells are more potent B cell activators compared to cbl/cbl-b competent TFH cells. There was increased plasmablast differentiation which secrete IgG. These data suggest that the deficiency of Cbl family in human elicits heightened T-dependent immune activation with augmentation of TFH responses, thus regulating humoral immune responses and the susceptibility to SLE in human. This project will advance our understanding of the mechanism of activation and maintenance of TFH cells in lupus and dissect possible avenues of therapeutic intervention in disease.