Anti-MS4a4B treatment abrogates MS4a4B-mediated protection in T cells and ameliorates experimental autoimmune encephalomyelitis |
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Authors: | Yaping Yan Zichen Li Guang-Xian Zhang Mark S Williams Gregory B Carey Jianke Zhang Abdolmohamad Rostami Hui Xu |
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Institution: | 1. Department of Neurology, Thomas Jefferson University, 900 Walnut Street, JHN 300, Philadelphia, PA, 19107, USA 2. Department of Microbiology and Immunology, University of Maryland School of Medicine, 800 W Baltimore Street, Baltimore, MD, 21201, USA 3. Department of Microbiology and Immunology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA, 19107, USA 4. Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Bethesda, MD, 20892, USA
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Abstract: | Recent data show that anti-CD20 therapy is effective for some autoimmune diseases, including multiple sclerosis (MS). However, the efficacy of anti-CD20 therapy for MS is largely limited because anti-CD20 antibodies target only B cells. In previous studies, we have investigated the function of MS4a4B, a novel CD20 homologue, in T cell proliferation. Here, we found that MS4a4B regulates not only T cell proliferation but also T cell apoptosis. Knockdown of MS4a4B by MS4a4B-siRNA or MS4a4B-shRNA-expressing vector promoted apoptosis in primary T cells and T32 cell line. In contrast, vector-driven over-expression of MS4a4B reduced apoptosis in EL-4 cells. Machinery analysis showed that MS4a4B-mediated T cell survival was associated with decreased activity of caspases 3, 8 and 9. Interestingly, binding of anti-MS4a4B antibodies to T cells induced activated T cells to undergo apoptosis. To test whether anti-MS4a4B antibody interferes with MS4a4B-mediated protection of T cells, we injected anti-MS4a4B antibodies into mice with experimental autoimmune encephalomyelitis (EAE). The results show that anti-MS4a4B treatment ameliorated the severity of EAE, accompanied by decreased Th1 and Th17 cell responses and reduced levels of pro-inflammatory cytokines in the central nervous system, suggesting that MS4a4B may serve as a target of antibody-based therapy for T cell-mediated diseases. |
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