Linking immunodeficiency with lymphomagenesis: suboptimal T follicular subsets can drive DLBCL transformation 4761

Abstract Description Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy derived from transformed B cells of germinal center (GC) or post-GC origin. DLBCL incidence is elevated in immunodeficient persons with reduced T cells, such as among HIV+ patients. Yet a causal link between T cell deficiency and DLBCL is incompletely understood. Using a mouse model of spontaneous DLBCL, we show that suboptimal T cell function, but neither zero nor full T cell function, can be a driver of B cell lymphomagenesis. In CD3δ-/- mice, which exhibit reduced number, signaling, and function of T cells, we observed progressive disruption of splenic architecture and eventual DLBCL development with ∼100% incidence. In contrast, lymphoma did not develop in wild-type mice, or CD3e-/-z-/- mice with complete T cell absence. This showed that poor-but-positive suboptimal T cells were required for GC B cell transformation and outgrowth. Mechanistically, CD3δ-/- mice exhibited altered GC dynamics at steady state and in response to immunization. Compared with wild-type mice, CD3δ-/- mice had a diminished T follicular regulatory (TFR) compartment and exhibited defective T follicular helper (TFH) cell differentiation when antigen challenged, indicating compromised regulation of the GC reaction. Indeed, defective GC B cell entry and differentiation was also observed. Our data thus suggest that suboptimal function of T helper subsets can lead to dysegulated GC reactions and B cell lymphomagenesis. Funding Sources Supported by AAI Intersect Fellowship Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)