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Immunol."],"abstract":"<jats:p>TET proteins mediate DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other oxidative derivatives. We have previously demonstrated a dynamic enrichment of 5hmC during T and invariant natural killer T cell lineage specification. Here, we investigate shared signatures in gene expression of <jats:italic>Tet2\/3<\/jats:italic> DKO CD4 single positive (SP) and iNKT cells in the thymus. We discover that TET proteins exert a fundamental role in regulating the expression of the lineage specifying factor Th-POK, which is encoded by <jats:italic>Zbtb7b<\/jats:italic>. We demonstrate that TET proteins mediate DNA demethylation - surrounding a proximal enhancer, critical for the intensity of Th-POK expression. In addition, TET proteins drive the DNA demethylation of site A at the <jats:italic>Zbtb7b<\/jats:italic> locus to facilitate GATA3 binding. GATA3 induces Th-POK expression in CD4 SP cells. Finally, by introducing a novel mouse model that lacks TET3 and expresses full length, catalytically inactive TET2, we establish a causal link between TET2 catalytic activity and lineage specification of both conventional and unconventional T cells.<\/jats:p>","DOI":"10.3389\/fimmu.2022.940995","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T08:16:51Z","timestamp":1659687411000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["TET proteins regulate T cell and iNKT cell lineage specification in a TET2 catalytic dependent 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