Location-directed functions of CD11c in regulating B cell tolerance 2259136

Abstract Introduction Autoimmunity, aging and infection drive aberrant accrual of CD11c+ B cells. CD11c (integrin α ITGAX), is classically defined as a dendritic cell marker and functions as both a complement receptor (CR4) and an integrin. However, its characterization on B cells remain limited. Single nucleotide polymorphisms near ITGAX locus have been identified as risk alleles for systemic lupus erythematosus (SLE), and patients with severe SLE exhibit marked expansion of CD11c+ B cells. These findings underscore the need to define B cell-intrinsic functions of CD11c in autoimmunity. Given the debated functional and developmental heterogeneity within CD11c+ B cells, we hypothesized that CD11c exerts multifaceted roles in maintaining B cell tolerance and homeostasis. Methods Using adoptive transfer and mixed bone marrow chimera models with CD11c deficient mice, we identified CD11c as a potential checkpoint of B cell tolerance. Results B cell-intrinsic CD11c deficiency impaired mature B cell recirculation to the bone marrow yet promoted spontaneous autoreactive germinal center development and autoantibody production within the autoimmune milieu of global CD11c deletion. We propose that CD11c restricts the peripheral release of proto-autoreactive B cells, thereby serving as a central tolerance regulator. Furthermore, splenic CD11c+ B cells displayed enhanced proliferation relative to their CD11c- counterparts, underscoring the context-dependent functions of CD11c in autoimmunity. Conclusion Together, these findings reveal tissue-specific roles of CD11c in shaping B cell fate, providing new insight into mechanisms of B cell tolerance and autoimmune pathology. Funding Source Canadian Institutes of Health Research (CIHR) Doctoral Foreign Study Award 202110DFD-475148-94277; National Institutes of Health (NIH) grants R01AR074105 and R01AI130307; Lupus Research Alliance Lupus Mechanisms and Targets Award Topic Categories Basic Autoimmunity (BA)