Targeting transcription cofactor OCA-B specifically blocks pancreatic T cell infiltration, cytokine production and elevated glucose in the NOD mouse model of type-1 diabetes (T1D)

Abstract

Abstract Type 1 Diabetes (T1D) is an autoimmune disease in which the host immune system is misdirected towards antigens associated with beta cells of the endocrine pancreas. In CD4 T cells, OCA-B (Pou2af1/OBF-1/Bob.1) promotes memory T cell function via the maintenance of poised gene expression states at multiple direct immunomodulatory target genes (e.g. Il2, Il21, Ifng, and Il2ra). OCA-B ensures poised gene expression states by recruiting the histone lysine demethylase Jmjd1a/Kdm3a. OCA-B is not expressed in naïve CD4 T cells, but becomes stably expressed upon stable antigen exposure. Memory T cell phenotypes can promote autoimmunity (including T1D), even in cases of persistent self-antigens. Consistently, OCA-B levels are strongly elevated in central memory CD4 T cells, but are even more elevated in islet-reactive, pancreas-infiltrating CD4 T cells in T1D. GWAS studies associate human polymorphisms in binding sites for Oct1, the transcription factor with which OCA-B docks, in autoimmunity generally and T1D in particular. Using a rationally-designed peptide inhibitor of OCA-B downstream effector function, we observe robust improvement in glucose levels in NOD mice genetically pre-disposed to T1D. In contrast, control peptides have no effect. The therapeutic benefit is associated with reductions in pancreatic-infiltrating CD4 and CD8 T cell numbers and cytokine production. In contrast, T cell numbers in pancreatic lymph nodes (PLNs) are normal, suggesting that non-self-directed immune function is largely intact. Our results show that OCA-B promotes pro-inflammatory T cell phenotypes needed in T1D and that it can be targeted pharmacologically.