Splenic T-bet+ B cells exhibit stem-like features and constitutively generate antibody-secreting cells

Abstract

Abstract T-bet-expressing B cells (a.k.a. Age-Associated B cells or atypical B cells) directly contribute to antiviral and autoimmune responses and thus represent a promising target for immunomodulatory therapies. T-bet+ memory B cells (MBCs) form and persist long term in the spleen as a resident subset; however, the functional role of this tissue-based population and mechanisms for its maintenance are poorly understood. Here, we use T-bet reporter and fate mapping mouse models to investigate the homeostasis and fate of T-bet+ B cell subsets. We identified an elevated turnover rate of T-bet+ MBCs, with ~1.5% of the population labeling with BrdU per day and 5–10% of T-bet+ MBCs in cell cycle (G1 or S) at any given time. T-bet+ MBCs also displayed resistance to sub-lethal irradiation. Fate mapping and adoptive transfer studies demonstrate that splenic T-bethigh B cells (Tbet++ CD11c+) spontaneously give rise to T-betlow (Tbet+ CD11c−) and ultimately a variety of effector B cell subsets, including GCB-like cells, plasma cells, and T-bet− memory-like B cells, absent exogenous challenge or stimulation. T-bet+ MBCs preferentially give rise to short-lived (CD138+ B220+) versus long-lived (CD138+ B220−) bone marrow and splenic plasma cells, and adoptively transferred T-bet+ MBCs are sufficient to generate plasma IgG2c titers in IgG2a-haptolype naïve recipients. Considering their long-term maintenance in the spleen, these findings suggest T-bet+ MBCs represent a self-renewing, stem-like pool that contribute to the maintenance of antibody titers by constitutive differentiation into antibody-secreting cells.