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

• Published in: The Journal of experimental medicine Vol. 218; no. 3
• Main Authors: Kim, Heejoo, Perovanovic, Jelena, Shakya, Arvind, Shen, Zuolian, German, Cody N, Ibarra, Andrea, Jafek, Jillian L, Lin, Nai-Pin, Evavold, Brian D, Chou, Danny H-C, Jensen, Peter E, He, Xiao, Tantin, Dean
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01-03-2021
• Subjects: Alleles; Amino Acid Sequence; Animals; Autoantigens - immunology; Autoimmunity; 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; 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
• ISSN: 0022-1007; 1540-9538
• 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.