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.
Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes
Disclosures: D. Tantin reported a patent (62/666,325). No other disclosures were reported.
H. Kim’s present address is Johnson & Johnson Research and Development, San Diego, CA.
A. Shakya’s present address is Bristol Myers Squibb, San Diego, CA.
D.H.-C. Chou’s present address is Department of Pediatrics, Division of Endocrinology and Diabetes, Stanford University School of Medicine, Palo Alto, CA.
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Heejoo Kim, Jelena Perovanovic, Arvind Shakya, Zuolian Shen, Cody N. German, Andrea Ibarra, Jillian L. Jafek, Nai-Pin Lin, Brian D. Evavold, Danny H.-C. Chou, Peter E. Jensen, Xiao He, Dean Tantin; Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes. J Exp Med 1 March 2021; 218 (3): e20200533. doi: https://doi.org/10.1084/jem.20200533
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