Location-directed functional dichotomy of CD11c in regulating B cell tolerance 3399

Abstract Description Autoimmunity, aging and infection drive aberrant accrual of CD11c+ B cells. CD11c, or integrin ∝X (ITGAX), is a classic dendritic cell marker with dual identities of a complement receptor (CR4) and an integrin receptor. However, its functions on B cells remain elusive. Single nucleotide polymorphisms near ITGAX loci were identified as systemic lupus erythematosus (SLE) risk alleles. Additionally, patients with severe SLE demonstrated prominent accumulation of CD11c+ B cells. These findings underscore the need for functional characterization of B cell-intrinsic CD11c in autoimmunity. The debated functional and developmental heterogeneity within CD11c+ B cells suggest multifaceted roles of CD11c in maintaining B cell homeostasis. Using adoptive transfer and mixed bone marrow chimera models, we found that CD11c is critical for both central and peripheral tolerance maintenance. In the bone marrow, CD11c deficiency compromised mature B cell development yet supported spontaneous autoimmune germinal center development and autoantibody production. Splenic CD11c+ B cells demonstrated enhanced proliferation, while CD11c-deficient B cells failed to sustain in foreign naïve or autoimmune environments conferred by wild-type or 564Igi mice, respectively. These findings suggest that CD11c exerts functional dichotomy driven by tissue- and cell-specific expression. Understanding these location-specific mechanisms could uncover novel pathways regulating B cell tolerance and autoimmunity. Funding Sources Supported by NIH R01AR074105; R01AI130307; LRA: Lupus Mechanisms and Targets Award; CIHR Doctoral Foreign Study Award 202110DFD-475148-94277 Topic Categories Basic Autoimmunity (BA)