Idiotype-specific CD4+ T cells chronically stimulate autoreactive B cells to develop into B lymphomas in mice.

Autoimmunity increases the risk of developing B lymphoma in humans; however, the molecular mechanism(s) underlying this link remain(s) unexplained. Here, we develop a mouse model to dissect the contribution of Id-driven T-B collaboration and show that chronic interaction between B cells and CD4+ T cells first leads to autoimmunity and later to the development of B (and T) cell lymphomas. We find that serum autoantibodies and lymphoma B cell receptor (BCR) are related and have the same specificity for ubiquitous self-antigens (histone and nucleosome) (Signal 1). Self-reactive B lymphoma cells are helped by CD4+ T cells that recognize a lymphoma neoantigen, an MHC class II-presented Idiotypic (Id) peptide (Signal 2). The mechanism, called Id-driven T-B collaboration, results in relentless mutual stimulation of B and T cells with germinal center markers, autoimmunity, and finally, malignant transformation of either B or T cells. Our results thus indicate Id-driven T-B collaboration as a potential mechanism linking autoimmunity and the development of lymphomas.