Targeting Transcriptional Coregulator OCA-B/Pou2af1 Blocks Activated Autoreactive T Cells in the Pancreas and Type 1 Diabetes

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2020 Dec 9

PMID 33295943

Citations 8

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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

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Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes.

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