OCA-B promotes pathogenic maturation of stem-like CD4<sup>+</sup> T cells and autoimmune demyelination

Erik P. Hughes; Amber R. Syage; Elnaz Mirzaei Mehrabad; Thomas E. Lane; Benjamin T. Spike; Dean Tantin

doi:10.1172/JCI187862

OCA-B promotes pathogenic maturation of stem-like CD4⁺ T cells and autoimmune demyelination

Published April 29, 2025 - More info

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Abstract

Stem-like T cells selectively contribute to autoimmunity, but the activities that promote their pathogenicity are incompletely understood. Here, we identify the transcription coregulator OCA-B as a driver of the pathogenic maturation of stem-like CD4⁺ T cell to promote autoimmune demyelination. Using two human multiple sclerosis (MS) datasets, we show that POU2AF1, the gene encoding OCA-B, is elevated in CD4⁺ T cells from MS patients. We show that T cell-intrinsic OCA-B loss protects mice from experimental autoimmune encephalomyelitis (EAE) while preserving responses to viral CNS infection. In EAE models driven by antigen reencounter, OCA-B deletion nearly eliminates CNS infiltration, proinflammatory cytokine production and clinical disease. OCA-B-expressing CD4⁺ T cells of mice primed with autoantigen express an encephalitogenic gene program and preferentially confer disease. In a relapsing-remitting EAE model, OCA-B loss protects mice specifically at relapse. During remission, OCA-B promotes the expression of Tcf7, Slamf6, and Sell in proliferating CNS T cell populations. At relapse timepoints, OCA-B loss results in both the accumulation of an immunomodulatory CD4⁺ T cell population expressing Ccr9 and Bach2, and loss of pro-inflammatory gene expression from Th17 cells. These results identify OCA-B as a driver of pathogenic CD4⁺ T cells.

OCA-B promotes pathogenic maturation of stem-like CD4⁺ T cells and autoimmune demyelination

Erik P. Hughes,¹ Amber R. Syage,¹ Elnaz Mirzaei Mehrabad,² Thomas E. Lane,³ Benjamin T. Spike,² and Dean Tantin¹

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OCA-B promotes pathogenic maturation of stem-like CD4+ T cells and autoimmune demyelination

Erik P. Hughes,1 Amber R. Syage,1 Elnaz Mirzaei Mehrabad,2 Thomas E. Lane,3 Benjamin T. Spike,2 and Dean Tantin1

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OCA-B promotes pathogenic maturation of stem-like CD4⁺ T cells and autoimmune demyelination

Erik P. Hughes,¹ Amber R. Syage,¹ Elnaz Mirzaei Mehrabad,² Thomas E. Lane,³ Benjamin T. Spike,² and Dean Tantin¹