Oct1 and OCA-B in T cells are potent therapeutic targets for autoimmune diseases

Abstract

Abstract Oct1 and OCA-B function together in CD4 T cells to promote poised gene expression states in immunomodulatory target genes (e.g. Il2, Il21, Ifng, Icos and Cd25) via the recruitment of the histone lysine demethylase Jmjd1a/Kdm3a. Oct1 and OCA-B are also critical for the generation of functional CD4 memory T cells in response to pathogen infection. Memory T cell phenotypes can promote autoimmunity, even in cases of persistent self-antigen exposure. In GWAS, single nucleotide polymorphisms in Oct1 binding sites for multiple genes are associated with T1D and MS. These findings suggest that Oct1 and OCA-B could modulate autoimmunity. Using a new T cell-specific OCA-B conditional-deleted Non-obese diabetic (NOD) mouse model, we find that T cell specific OCA-B deletion completely protects the animals from T1D. This is associated with reductions in pathogenic, pancreatic-infiltrating T cell numbers and cytokine production. In contrast, pancreatic lymph node T cell function is normal, suggesting that non-self-directed immune function is largely intact. Moreover, we have developed OCA-B inhibitor peptides as novel therapy for T1D and shown these to be efficacious in NOD mice. In EAE, which is a model for MS, Oct1 loss in T cells decreases clinical scores, T cell infiltrate and cytokine production. However, using a JHMV intracranial infection model, Oct1 loss has only minimal effects in clinical scores, viral clearance, infiltrating immune cells and cytokine production. These results suggest a therapeutic window in which deleting these proteins blunts autoimmunity while keeping normal immune function largely intact.