T-bet regulates long-lived plasma cell development in an influenza model (IRM10P.604)

Abstract

Abstract Long-lived plasma cells (LLPC) arise from germinal center B cells (GCB). The transcription factor Bcl6, which is required for GCB cell survival, inhibits LLPC development by repressing the transcription factor Blimp1, which normally initiates LLPC development. To date, it is not clear how these opposing transcription factors are regulated in GCB cells. In T lymphocytes, the transcription factor T-bet modulates the balance between Blimp1 and Bcl6 and controls the subsequent differentiation of the T cells into memory and effector cells. When naïve B cells are activated in vitro with T helper 1 (Th1) cells, the B cells differentiate into antibody (Ab) secreting cells in a T-bet and IFNγ dependent manner. Therefore, we hypothesized that B cell intrinsic expression of T-bet would also be necessary for LLPC development following influenza A infection. We found that T-bet expression increased in GCB cells formed after flu infection and was highest within GCB cells expressing low levels of the PC marker CD138, suggesting that T-bet supports PC differentiation from GCB cells. In chimeric mice in which 50% of cells are T-bet-/-, T-bet-/- GCB cells expressed lower levels of Blimp1 and IRF4 than WT GCB cells. Furthermore, flu-specific Ab titers were attenuated in chimeric animals lacking T-bet selectively within the B lineage cells compared to control chimeras with WT B cells. These results support a role for T-bet in the development of LLPC following influenza infection.