O-GlcNAcylation stabilizes OCA-B to sustain humoral immunity

Abstract Protein O-GlcNAcylation is a nutrient-sensitive post-translational modification implicated in immune regulation, yet its role in humoral immunity is poorly defined. Here we show that O-GlcNAcylation is required for effective antibody production downstream of B-cell activation. Pharmacologic inhibition of O-GlcNAc transferase markedly reduced immunoglobulin secretion across T cell–dependent and T cell–independent stimulation conditions. This defect was associated with impaired accumulation of activated B cells, reflecting both diminished expansion and increased cell death, as well as suppression of plasmablast-associated transcriptional programs including BLIMP1 and IRF4. Class-switch–associated germline transcription was largely preserved, whereas productive expression of immunoglobulin transcripts and secreted antibodies was substantially reduced, indicating a failure to sustain high-output antibody production. Mechanistically, O-GlcNAcylation stabilized the transcriptional regulators OCT-1 and OCA-B by preventing proteasome-dependent degradation. Mutation of a predicted O-GlcNAc site on OCA-B reduced protein stability, and OCA-B depletion recapitulated key defects in differentiation-linked antibody output. Transcriptomic analyses revealed substantial overlap between gene programs affected by O-GlcNAc inhibition and OCA-B loss, alongside additional OCA-B–independent changes. In vivo, systemic OGT inhibition diminished antigen-specific antibody responses, reduced germinal center and plasma cell populations, and lowered OCT-1 and OCA-B protein abundance without broadly depleting lymphocytes. These findings identify O-GlcNAcylation as a metabolic regulatory layer that sustains humoral immunity by stabilizing transcriptional programs required for differentiation into antibody-secreting cells.