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OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE243727 | GEO | 2024/04/09

REPOSITORIES: GEO

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OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Bulk RNAseq]

Project description:The identification of druggable therapeutic targets that preferentially promote autoimmunity remains a key goal in the field. Recent work shows that populations of memory/stem-like T cells drive autoimmunity, but the factors that generate and sustain these populations are incompletely understood. The lymphocyte-restricted transcriptional cofactor OCA-B/Pou2af1 is a regulator of CD4+ T cell memory. Here we show that T cell-intrinsic loss of OCA-B protects mice from experimental autoimmune encephalomyelitis (EAE) in both chronic and relapsing-remitting mouse models while preserving acute responses to infection with a neurotropic coronavirus. In adoptive transfer EAE driven by antigen re-encounter, T cell-specific OCA-B loss largely eliminates Th1- and Th17-mediated CNS infiltration, proinflammatory cytokine production and disease. Using an OCA-B-mCherry reporter mouse, we show that OCA-B expressing CD4+ T cells within the CNS of mice with EAE preferentially display a memory-like phenotype. Transferring these OCA-Bhi memory-like CD4+ T cells preferentially confers disease, identifying OCA-B as a marker of encephalitogenic autoreactive CD4+ T cells. Notably, in a relapsing-remitting EAE model, OCA-B T cell-deficient mice show specific protection at relapse, highlighting the potential to target OCA-B in MS patients to limit disease progression. During remission, OCA-B promotes the expression of Tcf7, Slamf6, and Sell in proliferating T cell populations. At relapse, OCA-B loss results in the accumulation of an immunomodulatory CD4+ T cell population expressing Ccr9 and Bach2. These results highlight OCA-B as a driver of pathogenic stem-like T cells responsible for relapse and promising MS therapeutic target.

2024-04-09 | GSE243726 | GEO

OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Remission scRNAseq]

2024-04-09 | GSE243725 | GEO

OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Relapse scRNAseq]

2024-04-09 | GSE243724 | GEO

OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells

Project description:OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells

| PRJNA1019704 | ENA

OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Relapse scRNAseq]

Project description:OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Relapse scRNAseq]

| PRJNA1019707 | ENA

OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Bulk RNAseq]

Project description:OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Bulk RNAseq]

| PRJNA1019708 | ENA

OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Remission scRNAseq]

Project description:OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Remission scRNAseq]

| PRJNA1019709 | ENA

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

Project description:The molecular mechanisms leading to the establishment of immunological memory are inadequately understood, limiting the development of effective vaccines and durable antitumor immune therapies. Here, we show that ectopic OCA-B expression is sufficient to improve antiviral memory recall responses, while having minimal effects on primary effector responses. At peak viral response, short-lived effector T cell populations are expanded but show increased Gadd45b and Socs2 expression, while memory precursor effector cells show increased expression of Bcl2, Il7r, and Tcf7 on a per-cell basis. Using an OCA-B mCherry reporter mouse line, we observe high OCA-B expression in CD4+ central memory T cells. We show that early in viral infection, endogenously elevated OCA-B expression prospectively identifies memory precursor cells with increased survival capability and memory recall potential. Cumulatively, the results demonstrate that OCA-B is both necessary and sufficient to promote CD4 T cell memory in vivo and can be used to prospectively identify memory precursor cells.

| S-EPMC10907311 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-30 | GSE214310 | GEO

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

Project description: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.

| S-EPMC7731945 | biostudies-literature

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