Tet2 deficiency alters CD4⁺ T cell function and promotes T cell lymphoma with a T_FH cell immunophenotype

TET2 mutations are frequent in T_FH-derived lymphomas, but how epigenetic disruption initiates malignant T cell transformation is unclear. We generated Cd4^cre;Tet2^FL/FL mice, which developed aggressive T cell lymphoma (m-TCL) with a T_FH cell–like immunophenotype. Genome-wide transcriptomics and epigenetic profiling of Tet2^−/− CD4⁺ T cells prior to lymphoma development showed hyperactive TCR, PI3K signaling, and dysregulated T_H differentiation program, with proliferation promoting signal transduction at the lymphoma stage. Tet2 loss promoted hyperplasticity under in vitro conditions but favored conditional T_FH differentiation. Reduced 5-hmC levels at regulatory genomic elements, resulted in transcriptional rewiring of T_FH-associated genes, promoting ICOS(L)-mediated PI3K signaling. TET2-KO human CD4⁺ T cells showed conserved epigenetic changes with increased proliferation, decreased exhaustion, increased memory marker expression, and clonal expansion with restricted TCR repertoire under in vitro conditions. scRNA-seq revealed a persistent proliferative cluster characterized by elevated stem-like transcriptional features compared with WT counterparts. Tet2^−/− m-TCLs allografted into NSG mice showed a significant response to epigenetic (5-azacytidine) and PI3K inhibitors (duvelisib) alone or in combination.