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

Heejoo Kim1,2, Jelena Perovanovic1,2, Arvind Shakya1

  • 1Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT.

The Journal of Experimental Medicine
|December 9, 2020
PubMed

Insights

Targeting the transcriptional coregulator OCA-B (OCAB) in T cells can prevent autoimmune diabetes in mice. Pharmacologic inhibition of OCA-B also shows promise for treating this condition.

Area of Science:

  • Immunology
  • Molecular Biology
  • Endocrinology

Background:

  • Autoimmune diseases like diabetes involve T cell-mediated attacks on self-tissues.
  • The transcriptional coregulator OCA-B (OCAB) is implicated in T cell activation and gene expression.

Purpose of the Study:

  • To investigate the role of OCA-B in autoimmune diabetes pathogenesis.
  • To determine if targeting OCA-B can prevent or treat autoimmune diabetes.

Main Methods:

  • Generated T cell-specific OCA-B knockout mice on a diabetes-prone background (NOD/ShiLtJ).
  • Utilized autoantigen-specific mouse models (NY8.3) and monoclonal antigen models.
  • Administered rationally designed OCA-B peptide inhibitors to diabetic mice.

Main Results:

  • T cell-specific deletion of OCA-B protected mice from spontaneous autoimmune diabetes.
  • OCA-B loss reduced pathogenic CD8+ T cell specificities and induced anergic phenotypes in CD4+ T cells.
  • OCA-B peptide inhibitors normalized glucose levels and reduced inflammation in diabetic mice.

Conclusions:

  • OCA-B is a critical regulator of autoimmune diabetes.
  • Targeting OCA-B, through genetic deletion or pharmacologic inhibition, represents a potential therapeutic strategy for autoimmune diabetes.

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