TY - JOUR
T1 - SerpinB1 controls encephalitogenic T helper cells in neuroinflammation
AU - Hou, Lifei
AU - Rao, Deepak A.
AU - Yuki, Koichi
AU - Cooley, Jessica
AU - Henderson, Lauren A.
AU - Jonsson, A. Helena
AU - Kaiserman, Dion
AU - Gorman, Mark P.
AU - Nigrovic, Peter A.
AU - Bird, Phillip I.
AU - Becher, Burkhard
AU - Remold-O’Donnell, Eileen
PY - 2019/10/8
Y1 - 2019/10/8
N2 - 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 (TH) 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+ TH 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.
AB - 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 (TH) 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+ TH 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.
KW - Autoimmune
KW - Inflammatory arthritis
KW - Multiple sclerosis
KW - Pathogenic T helper cells
KW - Serpins
UR - http://www.scopus.com/inward/record.url?scp=85073051628&partnerID=8YFLogxK
U2 - 10.1073/pnas.1905762116
DO - 10.1073/pnas.1905762116
M3 - Article
C2 - 31548399
AN - SCOPUS:85073051628
SN - 0027-8424
VL - 116
SP - 20635
EP - 20643
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 41
ER -