T-bet+CD11c+ age-associated B cells resist BLyS- and CD20-targeted ablation in murine lupus models

B cell ablation strategies show promise for treating humoral autoimmune diseases, but their impact on pathogenic tissue-localized T-bet+CD11c+ age-associated B cells (ABCs) is poorly defined. We assessed whether mAb-mediated B cell depletion impacts ABCs and other splenic B cell subsets in two mouse models of lupus. Following disease onset, we injected NZBxNZWF1 mice (NZBWF1; n = 72) or bm12 chronic graft versus host disease mice (cGVHD; n = 59) with 0.2 mg or 1 mg of anti-BLyS (10F4), anti-CD20 (18B12), combined treatment, or saline. Spleens were harvested after two weeks and B cell subset representation was analyzed via flow cytometry. In the NZBWF1 model, lymphopenia and resistance to 10F4 and 18B12 that arose concomitant with disease onset complicated interpretation, as ablative activity was partial and variable in the follicular (FO) and marginal zone (MZ) pools. Conversely, the T-bet+CD11c+ ABC pool was unchanged or enlarged versus controls and was entirely refractory to antibody treatments. In the cGVHD model, both 10F4 and 18B12 treatments ablated nearly all FO B cells. MZ B cells were profoundly ablated by 10F4 but spared by 18B12 treatment, whereas 10F4 treatment spared a small, undefined subset of splenic B cells that was ablated by 18B12. In contrast, T-bet+CD11c+ ABCs were minimally impacted by either reagent alone or combined, regardless of dose. The spleen-resident T-bet+CD11c+ ABC pool resists anti-BLyS and anti-CD20 ablative treatment. These findings have implications for antibody-mediated ablative strategies in patients with autoimmune diseases.