The diagram illustrates the proposed model in which eIF3e-deficient pre-GCB cells instruct a TFH-like polarized microenvironment. CXCR5- and PD1-expressing TFH-like CD4 T cells in turn provide activation signals, including IL-4, to more B cells, thereby initiating further GC reactions and eIF3e ablation leading to a feedforward cycle. Activated bystander B cells that maintain eIF3 expression ultimately undergo lymphoproliferation and lymphomagenesis. Potential roles for (dying) B cell-derived autoantigens in the aberrant B–T cell interactions are indicated. Arrows show interactions between the indicated cell types and processes. Orange-highlighted elements depict questions arising from the work or mechanisms that may contribute to disease development.
Aberrant B–T cell interactions promote lymphomagenesis. eIF3e deficiency in pre-GCB cells increases their antigen-presentation and co-stimulatory capacities, including elevated MHCII, CD80, ICOSL, and OX40L. These aberrant B cells engage CD4+ T cells and promote their differentiation toward a TFH-like state with high IL-4 expression. IL-4–producing TFH-like cells further activate bystander B cells, which promote additional eIF3e ablation and reinforce ongoing B cell activation. Although eIF3e-deficient B cells exhibit intrinsic defects in survival and proliferation, the remodeled microenvironment sustains repeated rounds of cell activation and GC responses in eIF3e-proficient B cells as well. Over time, this feed-forward circuit facilitates lymphoproliferation and malignant transformation of eIF3e-proficient B cells.