• CD11C+ T-BET+ B CELLS IN INFECTION AND AUTOIMMUNITY

      Winslow, Gary; Levack, Russell (2020)
      CD11c+ T-bet+ B cells serve crucial roles in both protective immunity and autoimmunity.However, the ontogeny of these cells remains unclear, and strategies to target them in vivo have yet to be identified. Here, we demonstrate that developing CD11c+ T-bet+ B cells received help in the form of IL-21, IFN-γ, and CD40L from a population ofT follicular helper 1(TFH1)cells outside of formal germinal centers (GC). These TFH1cells provided help to developing CD11c+ T-bet+ B cells in two distinct phases: IFN-gwas provided early following infection, and CD40L was provided later. Unlike the TFH1cells, CD11c+ T-bet+ B cells required the GC-associated transcription factor Bcl-6 for their development, but not T-bet. While the CD11c+ B cells that arose in the absence of T-bet appeared nearly identical to their T-bet-competent counterparts,they did not switch to IgG2c. These data support a model where, in the absence of formal GCs, TFH1cells provide GC-like help to developing CD11c+ T-bet+ B cells and while T-bet is not required for the development of these T-bet+ B cells,it is required for appropriate class-switch recombination (CSR). Our work also demonstrates that mature CD11c+ T-bet+ B cells, which arise in both immunity and autoimmunity,wereeliminated following treatment with the adenosine 2a receptor (A2aR) agonist CGS-21680. Depletion of these CD11c+ T-bet+ B cells occurred in a B cell-intrinsic manner and was corelated with improved disease outcome in a mouse model of lupus. Preliminary data indicated that human CD11c+ B cells expressed the A2aR,and these cells were depleted following CGS-21680 treatment in vitro, suggesting that A2aR-agonistadministrationmay also be effective in the treatment of human autoimmune diseaseswhere CD11c+ Bcell play a role. Overall, this work provides novel insight into the development of T-bet+ B cells and identifies the first pharmacological approach to target these cells in vivo.