Signaling control of antibody isotype switching.

Class switch recombination (CSR) generates isotype-switched antibodies with distinct effector functions essential for mediating effective humoral immunity. CSR is catalyzed by activation-induced deaminase (AID) that initiates DNA lesions in the evolutionarily conserved switch (S) regions at the immunoglobulin heavy chain (Igh) locus. AID-initiated DNA lesions are subsequently converted into DNA double stranded breaks (DSBs) in the S regions of Igh locus, repaired by non-homologous end-joining to effect CSR in mammalian B lymphocytes. While molecular mechanisms of CSR are well characterized, it remains less well understood how upstream signaling pathways regulate AID expression and CSR. B lymphocytes express multiple receptors including the B cell antigen receptor (BCR) and co-receptors (e.g., CD40). These receptors may share common signaling pathways or may use distinct signaling elements to regulate CSR. Here, we discuss how signals emanating from different receptors positively or negatively regulate AID expression and CSR.