Type I Interferons Induce T Regulatory 1 Responses and Restrict Humoral Immunity during Experimental Malaria

• Published in: PLoS pathogens Vol. 12; no. 10; p. e1005945
• Main Authors: Zander, Ryan A, Guthmiller, Jenna J, Graham, Amy C, Pope, Rosemary L, Burke, Bradly E, Carr, Daniel J J, Butler, Noah S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2016; Public Library of Science (PLoS)
• Subjects: Acquisitions & mergers; Analysis; Animals; Biology and Life Sciences; Cloning; Colleges & universities; Cytokines; Departments; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Funding; Gene expression; Genetic aspects; Health aspects; Health sciences; Immunity, Humoral - immunology; Immunoglobulins; Immunology; Infections; Interferon; Interferon Type I - immunology; Lymphocytes; Malaria; Malaria - immunology; Medicine and Health Sciences; Mice, Inbred C57BL; Parasites; Pathogens; Plasmodium; Regulation; Research and Analysis Methods; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology; United States > US; Oklahoma
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005945

CD4 T cell-dependent antibody responses are essential for limiting Plasmodium parasite replication and the severity of malaria; however, the factors that regulate humoral immunity during highly inflammatory, Th1-biased systemic infections are poorly understood. Using genetic and biochemical approaches, we show that Plasmodium infection-induced type I interferons limit T follicular helper accumulation and constrain anti-malarial humoral immunity. Mechanistically we show that CD4 T cell-intrinsic type I interferon signaling induces T-bet and Blimp-1 expression, thereby promoting T regulatory 1 responses. We further show that the secreted effector cytokines of T regulatory 1 cells, IL-10 and IFN-γ, collaborate to restrict T follicular helper accumulation, limit parasite-specific antibody responses, and diminish parasite control. This circuit of interferon-mediated Blimp-1 induction is also operational during chronic virus infection and can occur independently of IL-2 signaling. Thus, type I interferon-mediated induction of Blimp-1 and subsequent expansion of T regulatory 1 cells represent generalizable features of systemic, inflammatory Th1-biased viral and parasitic infections that are associated with suppression of humoral immunity.