Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes

J Exp Med. 2021 Mar 1;218(3):e20200533. doi: 10.1084/jem.20200533.


The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice but diminished in monoclonal models specific to artificial or neoantigens. Rationally designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels and reduced T cell infiltration and proinflammatory cytokine expression in newly diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Animals
  • Autoantigens / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Crosses, Genetic
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / prevention & control
  • Disease Models, Animal
  • Female
  • Gene Deletion
  • Germ Cells / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • Lymph Nodes / metabolism
  • Lymphocyte Activation
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Ovalbumin
  • Pancreas / metabolism
  • Pancreas / pathology*
  • Peptides / pharmacology
  • Receptors, Antigen, T-Cell / metabolism
  • Spleen / pathology
  • T-Lymphocytes / immunology*
  • Trans-Activators / deficiency
  • Trans-Activators / metabolism*
  • Transcription, Genetic*


  • Autoantigens
  • Cytokines
  • Inflammation Mediators
  • Peptides
  • Pou2af1 protein, mouse
  • Receptors, Antigen, T-Cell
  • Trans-Activators
  • Ovalbumin