CD137L and CD4 T cells limit BCL6‐expressing pre‐germinal center B cell expansion and BCL6‐driven B cell malignancy

Aberrant expression of the proto‐oncogene BCL6 is a driver of tumorigenesis in diffuse large B cell lymphoma (DLBCL). Mice overexpressing BCL6 from the B cell‐specific immunoglobulin heavy chain μ intron promoter (Iμ‐Bcl6 (Tg/+)) develop B cell lymphomas with features typical of human DLBCL. While the development of B cell lymphoma in these mice is tightly controlled by T cells, the mechanisms of this immune surveillance are poorly understood. Here we show that CD4 T cells contribute to the control of lymphoproliferative disease in lymphoma‐prone Iμ‐Bcl6 (Tg/+) mice. We reveal that this CD4 T cell immuno‐surveillance requires signaling by the co‐stimulatory molecule CD137 ligand (CD137L; also known as 4‐1BBL), which may promote the transition of pre‐malignant B cells with an activated phenotype into the germinal center stage via reverse signaling, preventing their hazardous accumulation. Thus, CD137L‐mediated CD4 T cell immuno‐surveillance adds another layer of protection against B cell malignancy to that provided by CD8 T cell cytotoxicity.