Cd1d regulates B cell development but not B cell accumulation and IL10 production in mice with pathologic CD5⁺ B cell expansion

Background: CD1d is a widely expressed lipid antigen presenting molecule required for CD1d-restricted invariant natural killer T (iNKT) cell development. Elevated CD1d expression is detected in CD5⁺ IL10-producing B cells, called B10 B cells, and is correlated with poorer prognosis in chronic lymphocytic leukemia (CLL), a CD5⁺ B cell malignancy with B10-like functional properties. Whether CD1d expression regulates CD5⁺ B cell accumulation, IL10 competence, and antibody production in naïve mice with pathologic CD5⁺ B cell expansion remains untested. Results: Using three different transgenic mouse models of benign or leukemic CD5⁺ B cell expansion, we found that CD1d was differentially expressed on CD5⁺ B cells between the three models, but loss of CD1d expression had no effect on CD5⁺ B cell abundance or inducible IL10 expression in any of the models. Interestingly, in the CLL-prone Eμ-TCL1 model, loss of CD1d expression suppressed spontaneous IgG (but not IgM) production, whereas in the dnRAG1xEμ-TCL1 (DTG) model of accelerated CLL, loss of CD1d expression was associated with elevated numbers of splenic CD4⁺ and CD8⁺ T cells and an inverted CD4⁺:CD8⁺ T cell ratio. Unexpectedly, before leukemia onset, all three transgenic CD1d-deficient mouse strains had fewer splenic transitional B cells than their CD1d-proficient counterparts. Conclusions: The results show that CD1d expression and iNKT cells are dispensable for the development, accumulation, or IL10 competence of CD5⁺ B cells in mice prone to benign or leukemic CLL-like B cell expansion, but reveal a novel role for iNKT cells in supporting B cell progression through the transitional stage of development in these animals. These results suggest CD1d-directed therapies to target CLL could be evaded by downregulating CD1d expression with little effect on continued leukemic CD5⁺ B cell survival. The data also imply that iNKT cells help restrain pro-leukemic CD8⁺ T cell expansion in CLL, potentially explaining a reported correlation in human CLL between disease progression, the loss of NKT cells, and a paradoxical increase in CD8⁺ T cells.