Assessing the impact of TET2 and TET3 deletion in TCRa and TCRb expression and repertoire in murine CD4 T cells in physiological and pathological conditions [TCR-seq]

TET proteins are tumor suppressors that through their catalytic activity oxidize 5-methylcytosine to 5-hydroxymethylcytosine, to promote DNA demethylation and to regulate gene expression. Notably, TET2 is one of the most frequently mutated genes in hematological malignancies, including T cell lymphomas. However, murine models with deletion of TET2 do not exhibit T cell expansion, presumably due to redundancy with other members of the TET family of proteins. In order to gain insight on the TET mediated molecular events that safeguard T cells from aberrant proliferation we performed serial adoptive transfers of murine CD4 T cells that lack concomitantly TET2 and TET3 to fully immunocompetent congenic mice. Our data reveal a progressive acquisition of malignant traits upon loss of TET2 and TET3 that is characterized by loss of genomic integrity, acquisition of aneuploidy and upregulation of the protooncogene Myc. We evaluated TCRa and TCRb chain repertoire to assess clonality in control, Tet2/3 DKO CD4 SP, Tet2/3 DKO CD4 peripheral T cells as well as transferred and expanded cells