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

• DOI: 10.1101/2020.02.06.937839
• Publication Date: 2020-02-07T15:17:34Z
• Authors: 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
• Keywords: NOD mice

Abstract The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases repeated antigen exposure, a necessary feature autoimmunity. We hypothesized that cell-specific deletion and pharmacologic inhibition would protect mice from autoimmune diabetes. developed an Ocab conditional allele backcrossed it onto diabetes-prone NOD/ShiLtJ strain background. loss protected spontaneous disease. Protection was associated with large reductions islet CD8 + receptor specificities diabetes pathogenesis. CD4 clones were present, but anergic phenotypes. protective effect recapitulated using autoantigen-specific NY8.3 mice, diminished monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating peptide inhibitors normalized glucose levels, reduced infiltration proinflammatory cytokine newly-diabetic NOD mice. Together, the results indicate is potent regulator promising for inhibition. ~40-word summary statement online JEM table contents alerts Kim colleagues show cells essential generation type-1 leaves pancreatic lymph nodes largely undisturbed, associates autoreactive pancreas anergy while deleting potentially cells. Summary et al. protects