Semaphorin 4C Protects against Allergic Inflammation: Requirement of Regulatory CD138+ Plasma Cells

• Published in: The Journal of immunology (1950) Vol. 198; no. 1; pp. 71 - 81
• Main Authors: Xue, Di, Kaufman, Gabriel N, Dembele, Marieme, Beland, Marianne, Massoud, Amir H, Mindt, Barbara C, Fiter, Ryan, Fixman, Elizabeth D, Martin, James G, Friedel, Roland H, Divangahi, Maziar, Fritz, Jörg H, Mazer, Bruce D
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01.01.2017
• Subjects: Adoptive Transfer; Allergens; Allergic diseases; Alveoli; Animals; Autoimmune diseases; Axon guidance; B-Lymphocyte Subsets - immunology; Blotting, Western; Bone marrow; Bronchus; CD19 antigen; Cytokines; Cytokines - biosynthesis; Eosinophilia; Flight corridors; Flow Cytometry; Homeostasis; Hypersensitivity; Immune response; Immunoregulation; Inflammation; Interleukin 10; Interleukin 4; Interleukin 5; Leukocytes (eosinophilic); Lung diseases; Lungs; Lymphocyte receptors; Lymphocytes; Lymphocytes B; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Plasma cells; Plasma Cells - immunology; Pneumonia - immunology; Respiratory Hypersensitivity - immunology; Respiratory tract; Respiratory tract diseases; Semaphorins - immunology; Syndecan-1 - immunology; T cell receptors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600831

The regulatory properties of B cells have been studied in autoimmune diseases; however, their role in allergic diseases is poorly understood. We demonstrate that Semaphorin 4C (Sema4C), an axonal guidance molecule, plays a crucial role in B cell regulatory function. Mice deficient in Sema4C exhibited increased airway inflammation after allergen exposure, with massive eosinophilic lung infiltrates and increased Th2 cytokines. This phenotype was reproduced by mixed bone marrow chimeric mice with Sema4C deficient only in B cells, indicating that B lymphocytes were the key cells affected by the absence of Sema4C expression in allergic inflammation. We determined that Sema4C-deficient CD19 CD138 cells exhibited decreased IL-10 and increased IL-4 expression in vivo and in vitro. Adoptive transfer of Sema4c CD19 CD138 cells induced marked pulmonary inflammation, eosinophilia, and increased bronchoalveolar lavage fluid IL-4 and IL-5, whereas adoptive transfer of wild-type CD19 CD138 IL-10 cells dramatically decreased allergic airway inflammation in wild-type and Sema4c mice. This study identifies a novel pathway by which Th2-mediated immune responses are regulated. It highlights the importance of plasma cells as regulatory cells in allergic inflammation and suggests that CD138 B cells contribute to cytokine balance and are important for maintenance of immune homeostasis in allergic airways disease. Furthermore, we demonstrate that Sema4C is critical for optimal regulatory cytokine production in CD138 B cells.