SerpinB1 controls encephalitogenic T helper cells in neuroinflammation.

SerpinB1, a protease inhibitor and neutrophil survival factor, was recently linked with IL-17-expressing T cells. Here, we show that serpinB1 ( Sb1 ) is dramatically induced in a subset of effector CD4 cells in experimental autoimmune encephalomyelitis (EAE). Despite normal T cell priming, Sb1 ^-/- 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 Sb1 ^-/- 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 Sb1 deletion, dramatically reverts EAE, strongly indicating that the CXCR6 ⁺ T cells are the drivers of encephalitis.
Competing Interests: Conflict of interest statement: L.H. and E.R.-O. filed a provisional patent related to the findings of this study and have equity ownership and are on the Scientific Advisory Board of the recently launched Edelweiss Immune, Inc. The other authors declare no conflict of interest.