eIF3e-mediated translational checkpoint maintains immune tolerance and prevents lymphoid malignancy

Translational control is essential for immune function, but its roles in immune tolerance and lymphomagenesis remain poorly defined. Here, we show that Cγ1Cre-mediated deletion of Eif3e, which encodes a subunit of the eIF3 translation initiation complex, in B cells causes lymphoproliferation, malignant transformation of Eif3e-sufficient bystander lymphocytes, and premature death. Eif3e-deficient B cells upregulate the costimulatory molecule CD80, promoting CD4+ T cell activation and differentiation into IL-4-producing TFH-like cells. These cells, in turn, activate bystander B cells, increase MHC class II expression, and establish a feedforward loop of Eif3e deletion and lymphocyte activation. Despite their hyperactivated state, Eif3e-deficient B cells exhibit impaired proliferation, reduced survival, and defective differentiation. This self-amplifying circuit of aberrant B and T cell activation ultimately drives malignant transformation of Eif3e-sufficient lymphocytes. Our findings uncover an eIF3e-dependent translational checkpoint that preserves immune homeostasis and restrains lymphomagenesis.