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

TET2 mutations are frequent in TFH-derived lymphomas, but how epigenetic disruption initiates malignant T cell transformation is unclear. We generated Cd4cre;Tet2FL/FL mice, which developed aggressive T cell lymphoma (m-TCL) with a TFH 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 TH differentiation program, with proliferation promoting signal transduction at the lymphoma stage. Tet2 loss promoted hyperplasticity under in vitro conditions but favored conditional TFH differentiation. Reduced 5-hmC levels at regulatory genomic elements, resulted in transcriptional rewiring of TFH-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.