B cell TET2 recruits OGT for nuclear TET2 and H2B O-GlcNAcylation to drive AID and BLIMP-1 expression and maturation of the antibody response.

Maturation of antibody responses entails B cell Aicda/AID and Prdm1/BLIMP-1 expression for SHM/CSR, plasma cell differentiation, and production of class-switched high-affinity antibodies. We determined that TET1, TET2, and TET3 are not expressed in resting naïve B lymphocytes, and only TET2 is induced in differentiating B cells for AID and BLIMP-1 expression. B cell TET2 recruits OGT, a metabolic sensor and sole protein O-GlcNAcylator, for O-GlcNAcylation of itself and chromatin H2B-S112. TET2 O-GlcNAcylation supports TET2-mediated active DNA demethylation (5mC oxidation to 5hmC) of Aicda and Prdm1 loci. This, together with these loci H2B-S112 O-GlcNAcylation, promotes Aicda/AID and Prdm1/BLIMP-1 expression for maturation of T-dependent and T-independent antibody responses. TET2 recruits OGT through its C-terminal-end, as evidenced by Tet2OGT-Δmut C-terminal-end deletion mutant and AlphaFold 3.0-modeled TET2-DNA-OGT complex. Finally, B cell TET2 takes metabolic cues for Aicda/AID and Prdm1/BLIMP-1 expression, as shown by fumarate inhibition and vitamin C activation of TET2 in humanized THX mice and Tcrβ-/-Tcrδ-/- mice.