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

Abstract

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.

Construction and Validation of a Tumor Microenvironment-Based Scoring System to Evaluate Prognosis and Response to Immune Checkpoint Inhibitor Therapy in Lung Adenocarcinoma Patients

“…MS4A1 encodes the CD20 protein (Tedder et al, 1988), which is the target of active drugs for the treatment of autoimmune diseases such as rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab. OCA-B protein encoded by POU2AF1 promotes the expression of T-cell target genes in the presence of repeated antigen exposure (Kim et al, 2021). These explain the validity and reliability of the TMERSscore in predicting the prognosis of LUAD patients and in assessing the response to immunotherapy.…”

Construction and Validation of a Tumor Microenvironment-Based Scoring System to Evaluate Prognosis and Response to Immune Checkpoint Inhibitor Therapy in Lung Adenocarcinoma Patients

“…MS4A1 encodes the CD20 protein [ 50 ], which is the target of active drugs for the treatment of autoimmune diseases such as rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab. The OCA-B protein encoded by POU2AF1 promotes the expression of T-cell target genes in the presence of repeated antigen exposure [ 51 ]. These explain the validity and reliability of the TMERSscore in predicting the prognosis of LUAD patients and in assessing the response to immunotherapy.…”

OCA-B/Pou2af1 is sufficient to promote CD4+T cell memory and prospectively identifies memory precursors

“…All animal experiments were approved by the University of Utah Institutional Animal Care and Use Committee (17-05008). Pou2af1 ( Ocab ) conditional (floxed) mice were described previously (Kim et al ., 2021). Pou2af1 -3 mCherry reporter knock-in mice were generated on a C57BL/6N background (Biocytogen), but all subsequent mouse crosses (>5 prior to generation of data herein) were to C57BL/6J.…”

“…Elevated levels of Ocab ( Pou2af1 ) mRNA are seen in CD4 + CD25 lo early effector cells that are enriched for the ability to form memory after viral clearance (Snook et al, 2018). T cell-specific OCA-B knockout using a conditional mouse allele strongly attenuates spontaneous autoimmune diabetes, with autoreactive TCR specificities in pancreas either deleted or associated with anergy (Kim et al, 2021). Cumulatively, these findings demonstrate potent roles for OCA-B in antigen recall response, immune memory and autoimmunity.…”