| Description |
In CD4+ T cells, Oct1/OCA-B interaction promotes poised gene expression states in the immunomodulatory target genes through the recruitment of the histone lysine demethylase Jmjd1a/Kdm3a. OCA-B is not expressed in naïve mouse CD4+ T cells, but becomes stably expressed upon persistent antigen exposure which is not only a common feature of autoimmunity, but is also critical for the functional memory T cells formation. This study reveals that Oct1 and OCA-B have critical roles in T cell memory and autoimmunity. In a natural polyclonal response to viral infection, it is shown that OCA-B expression in T cells is critical for memory cell formation. Moreover, ectopic OCA-B expression does not affect primary effector responses, but is sufficient to induce T cells towards a long-lived memory fate in a chimeric mouse model using transduced SMARTA cells. Ectopically expressing OCA-B upregulates the expression levels of surface markers associated with memory T cells such as CD62L. In addition, Oct1 deletion in T cells protects animals from autoimmune diseases with intact responses to pathogens. Oct1 conditional deletion in T cells decreases clinical scores and infiltration of cytokine-producing T cells in an experimental autoimmune encephalomyelitis (EAE) model despite anti-viral T cell effector functions that are normal in the absence of Oct1. Consistently, Oct1-deficient CD4+ T cells stimulated in vitro showed increased expression of markers associated with T cell anergy. It is also clarified that deletion of OCA-B protects diabetes-prone mice from type 1 diabetes (T1D) development using novel NOD background Ocab iv whole-body-deleted mice and Ocab conditional mice. Protection was associated with reduced macrophage infiltration, and reduced proinflammatory cytokine expression of cytotoxic T cells in the pancreata. Rationally-designed membrane-penetrating OCA-B peptide inhibitors are developed and tested in the NOD mouse model. Pharmacologic OCA-B inhibition normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results in this study indicate that Oct1 and OCA-B are critical regulators of T cell memory responses and can be a promising target of pharmacologic inhibition for autoimmunity. |
