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Stem-like T cell populations can selectively contribute to autoimmunity, but the activities that promote and sustain these populations are incompletely understood. Here, we show that T cell-intrinsic loss of the transcription cofactor OCA-B protects mice from experimental autoimmune encephalomyelitis (EAE) while preserving responses to CNS infection. In adoptive transfer EAE models driven by multiple antigen encounters, OCA-B deletion nearly eliminates CNS infiltration, proinflammatory cytokine production and clinical disease. OCA-B-expressing CD4 + T cells within the CNS of mice with EAE comprise a minority of the population but display a memory phenotype and preferentially confer disease. In a relapsing-remitting EAE model, OCA-B T cell deficiency specifically protects mice from relapse. During remission, OCA-B promotes the expression of Tcf7 , Slamf6 , and Sell in proliferating T cell populations. At relapse, OCA-B loss results in both the accumulation of an immunomodulatory CD4 + T cell population expressing Ccr9 and Bach2 , and the loss of pro-inflammatory gene expression from Th17 cells. These results identify OCA-B as a driver of pathogenic stem-like T cells.

Breast cancers are categorized into subtypes with distinctive therapeutic vulnerabilities and prognoses based on their expression of clinically targetable receptors and gene expression patterns mimicking different cell types of the normal gland. Here, we tested the role of Mcam in breast cancer cell state control and tumorigenicity in a luminal progenitor-like murine tumor cell line (Py230) that exhibits lineage and tumor subtype plasticity. Mcam knockdown Py230 cells show augmented Stat3 and Pi3K/Akt activation associated with a lineage state switch away from a hormone-sensing/luminal progenitor state toward alveolar and basal cell related phenotypes that were refractory to growth inhibition by the anti-estrogen therapeutic, tamoxifen. Inhibition of Stat3, or the upstream activator Ck2, reversed these cell state changes. Mcam binds Ck2 and acts as a regulator of Ck2 substrate utilization across multiple mammary tumor cell lines. In Py230 cells this activity manifests as increased mesenchymal morphology, migration, and Src/Fak/Mapk/Paxillin adhesion complex signaling in vitro , in contrast to Mcam's reported roles in promoting mesenchymal phenotypes. In vivo , Mcam knockdown reduced tumor growth and take rate and inhibited cell state transition to Sox10+/neural crest like cells previously been associated with tumor aggressiveness. This contrasts with human luminal breast cancers where MCAM copy number loss is highly coupled to Cyclin D amplification, increased proliferation, and the more aggressive Luminal B subtype. Together these data indicate a critical role for Mcam and its regulation of Ck2 in control of breast cancer cell state plasticity with implications for progression, evasion of targeted therapies and combination therapy design., Competing Interests: Competing interests: The authors declare no conflict of interest exists.