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Significance The study addresses a basic immunology topic with considerable clinical relevance, namely the nature of the pathogenic T helper cells that drive autoimmune disorders like multiple sclerosis (MS) and inflammatory arthritis. Using mouse MS, we identify precursors of the encephalitogenic/pathogenic T cells based on their dependence on the protease inhibitor SerpinB1. Newly identified signature genes reveal the unusual nature of these T cells that combine (i ) inflammatory cytokine secretion, (ii ) a cytolytic system, and (iii ) extreme rapid proliferation. We demonstrate that their survival/expansion depends on SerpinB1 and involves regulation of a proliferation-associated protease-mediated cell suicide mechanism. Importantly, we discovered that cell surface CXCR6 is an exquisite marker of pathogenic T helper cells and demonstrated that anti-CXCR6 treatment has potential to prevent or mitigate MS.

SerpinB1 controls encephalitogenic T helper cells in neuroinflammation