Targeting OCA-B/Pou2af1 blocks type-1 diabetes and reduces infiltration of activated, islet-reactive T cells
bioRxiv (Cold Spring Harbor Laboratory)(2020)
Abstract
Autoimmune therapies aim to inhibit autoreactivity while preserving normal immune function. The transcriptional coregulator OCA-B, also known as Bob.1/OBF-1 (gene symbol Pou2af1) is induced in stimulated naive CD4+ T cells, where it docks with transcription factor Oct1 to regulate genes such as Il2 and Ifng. OCA-B promotes expression of these targets in cases of repeated antigen exposure, a necessary feature of autoimmunity. Polymorphisms in Ocab itself and binding sites for Oct1/OCA-B complexes are associated with multiple forms of autoimmunity including autoimmune (type-1) diabetes. We hypothesized that T cell-specific OCA-B deletion would protect mice from type-1 diabetes, and that pharmacologic OCA-B inhibition would provide similar protection. 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 T1D. Protection was associated with reduced pancreatic T cell and macrophage infiltration and reduced proinflammatory cytokine expression. We profiled prediabetic pancreatic lymph nodes and islets by single-cell RNA sequencing and T cell receptor clonotype analysis. Although lymph nodes showed minimal differences, in the islets CD8+ T cell specificities associated with diabetes pathogenesis failed to emerge in OCA-B deficient activated/memory cells. In contrast, CD4+ clones associated with diabetes were present, but only in anergic cells. The protective effect of OCA-B loss was diminished, or even eliminated, using monoclonal models with high affinity 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.
MoreTranslated text
Key words
diabetes,islet-reactive
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined