Excessive CD11c+Tbet+ B cells promote aberrant TFH differentiation and affinity-based germinal center selection in lupus

Significance The paradoxical coexistence of excessive autoantibodies and inadequate affinity-matured pathogen-specific antibodies in lupus is poorly understood. Here, we found that excessive CD11c+T-bet+ age-associated B cells (ABCs)—a recently described autoimmunity-relevant B cell subset [K. Rubtsova et al., J. Clin. Invest. 127, 1392–1404 (2017)]—not only contribute to the production of autoantibodies but also promote aberrant follicular T-helper (TFH) cell differentiation and consequently compromise affinity-based germinal center (GC) B-cell selection and antibody-affinity maturation in lupus mouse models. Importantly, ablating B cell-intrinsic Toll-like receptor (TLR) signaling adaptor MyD88 in lupus mice inhibited CD11c+T-bet+ ABC differentiation, normalized TFH differentiation, and rescued GC selection, as well as prevented autoantibody production, suggesting that CD11c+T-bet+ ABCs and TLR signaling are potential targets for lupus treatment. Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response―a process critical for antibody affinity maturation―is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c+Tbet+ age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c+Tbet+ ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c+Tbet+ ABCs and deregulated TFH cell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c+Tbet+ ABC differentiation, and blocking CD11c+Tbet+ ABC differentiation in ShipΔB mice by ablating MyD88 normalizes TFH cell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c+Tbet+ ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.