OCA-B/Pou2af1 promotes autoimmune demyelination through control of stem-like CD4+ T cells [Remission scRNAseq]
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. Overall design: NOD Ocab(fl/fl) and Ocab(fl/fl);CD4-Cre mice were induced with EAE. At disease remission, brain and spinal cord CD3e+ cells were isolated by FACS and processed for single cell RNA sequencing.