Introduction/Rationale: Autophagy is a highly conserved cellular degradation process that delivers cytoplasmic products to lysosomes for recycling. While studies have implicated autophagy-related factors in B cell biology, the relative contribution of noncanonical versus canonical autophagy has remained unclear. To more directly determine the role of macroautophagy to B cell homeostasis and function, we focused on Fip200, a scaffold protein that solely licenses canonical autophagy.
Methods: We generated a murine model with B cell-specific Fip200-deficiency using a CD19-Cre driver cassette, hereafter referred to as Fip200∆B mice.
Results: Fip200∆B mice showed normal B2 cell development and maintenance but a major defect in peritoneal B1a cells. Surprisingly, mutant mice displayed accumulated T cell populations in the secondary lymphoid organs and circulation, accompanied by altered thymic T cell development. Additionally, Fip200-deficient B cells displayed a hyperactivated phenotype with elevated basal CD86 and CD80 expression, which may promote T cell expansion. Consistent with prior studies, Fip200∆B mice generated an intact primary immune response upon T cell-dependent immunization, yet developed impaired primary antibody production and maintenance. Despite lower pre-boost antibody titers, mutant animals mounted enhanced recall responses, with elevated antigen-specific germinal center B cells, memory B cells, and IgG2c. Lastly, Fip200 deficiency increased the formation and in vitro differentiation of age-associated B cells (ABCs). Mechanistically, defective mitochondrial respiration and mitochondrial clearance drove the expansion of ABCs in mutant mice. In an induced model of murine lupus, Fip200 deficiency attenuated disease severity, implicating B cell canonical autophagy in the pathogenesis of murine lupus-like disease.
Conclusion: Our findings identify B cell canonical autophagy as a critical mediator that calibrates the B and T cell compartment and immune responsiveness while constraining autoimmune pathogenicity.
