ATM influences germinal center integrity

The DNA damage response protein ATM has long been known to influence class switch recombination (CSR) in ex vivo cultured B cells. However, an assessment of B cell-intrinsic requirement of ATM in humoral responses in vivo was confounded by the fact that its germline deletion affects T cell function, and B:T cell interactions are critical for in vivo immune responses. Here we demonstrate that B cell-specific deletion of ATM in mice leads to reduction in germinal center (GC) frequency and size in response to immunization. We find that loss of ATM induces apoptosis of GC B cells, likely due to unresolved DNA lesions in cells attempting to undergo CSR. Accordingly, suboptimal GC responses in ATM-deficient animals are characterized by decreased titers of class switched antibodies and decreased rates of somatic hypermutation. These results unmask the critical B cell intrinsic role of ATM in maintaining an optimal GC response following immunization.