Translocation of the oncogene Bcl6 in humans is considered to be highly related to the lymphomagenesis of diffuse large B cell lymphoma (DLBCL). This is supported by a transgenic mouse strain (Bcl6Tg/+) bearing a translocated BCL6-coding sequence and developing B cell lymphoma with features typical of DLBCL (1).
Although CD8 T cells can efficiently kill BCL6-driven B lymphoma cells (2), we found that Bcl6Tg/+ mice lacking CD8 T cells (Bcl6Tg/+CD8-/-) had a survival rate similar to intact Bcl6Tg/+ mice, suggesting that the existence of other immune surveillance besides CD8 T cells. Our RNA-sequencing analysis indicated that B cells expressing CD137 ligand (CD137L) are the origin of one type of BCL6-driven B cell lymphoma developing in the absence of T cells. Given that CD137L is a bidirectional signaling molecule that not only activates T cells when binding to its receptor, CD137, but also reverse signals into the cells expressing CD137L, we hypothesize that CD137L-mediated reverse signaling can suppress BCL6-driven B cell lymphoma in the absence of CD8 T cells. Indeed, Bcl6Tg/+CD8-/- mice treated with the anti-CD137L blocking antibody for 12 weeks showed signs of lymphoproliferative diseases and a 10-fold expansion of a highly proliferating B-cell population with a CD86+IgDlo, activated B-cell phenotype. Moreover, when CD4 T cells, of which the activated state expresses CD137, were depleted in Bcl6Tg/+CD8-/- mice for 12 weeks, we found an expansion of a B cell population with a similar activated phenotype. In addition, crosslinking CD137L on B cells by a recombinant CD137 protein facilitated the further differentiation of Bcl6Tg/+ B cells in vitro.
Therefore, we conclude that CD137L-mediated reverse signaling prevents the hazardous accumulation of the CD86+IgDlo premalignant B cells in BCL6-driven lymphomagenesis by promoting their differentiation into the next stage of development upon CD137 ligation.