Control of antibody class switch recombination by quantitative integration of antigen signaling.

Immunoglobulin class switch recombination by B lymphocytes requires the simultaneous expression of activation-induced cytidine deaminase (AID) and noncoding germline transcripts (GLT). Expression of both components is controllable through cytokine signalling and arise through stochastic mechanisms linked to cell division that can be predicted in mathematical models. Here we demonstrate that the same principles govern the mathematically predictable antigen-mediated regulation of isotype switching. We report both antigen affinity and antigen concentration regulated rates of AID expression and germline transcription with varying sensitivities and division-linked mechanisms. A model incorporating AID and germline transcript expression accurately predicted the rates of class switching in B cells across varying antigen affinities and dosages. Thus, class switch recombination is governed by a universal molecular logic that allows cytokine and antigen induced signals to be incorporated into a single predictive mathematical model that is robust to variable external signals to which B cells are exposed.