SerpinB1 controls encephalitogenic T helper cells in neuroinflammation.

Abstract

SerpinB1, a protease inhibitor and neutrophil survival factor, was recently linked with IL-17-expressing T cells. Here, we show that <i>serpinB1</i> (<i>Sb1</i>) is dramatically induced in a subset of effector CD4 cells in experimental autoimmune encephalomyelitis (EAE). Despite normal T cell priming, <i>Sb1</i>^-/- mice are resistant to EAE with a paucity of T helper (T_H) cells that produce two or more of the cytokines, IFNγ, GM-CSF, and IL-17. These multiple cytokine-producing CD4 cells proliferate extremely rapidly; highly express the cytolytic granule proteins perforin-A, granzyme C (GzmC), and GzmA and surface receptors IL-23R, IL-7Rα, and IL-1R1; and can be identified by the surface marker CXCR6. In <i>Sb1</i>^-/- mice, CXCR6⁺ T_H cells are generated but fail to expand due to enhanced granule protease-mediated mitochondrial damage leading to suicidal cell death. Finally, anti-CXCR6 antibody treatment, like <i>Sb1</i> deletion, dramatically reverts EAE, strongly indicating that the CXCR6⁺ T cells are the drivers of encephalitis.