title: MyD88 signaling in CD4 T cells promotes IFN-γ production and hematopoietic progenitor cell expansion in response to intracellular bacterial infection.
abstract: Hematopoietic stem and progenitor cell (HSPC) phenotype and function can change in response to infectious challenge. These changes can be mediated by cytokines, IFNs, and pathogen-associated molecules, via TLR, and are thought to promote tailored immune responses for particular pathogens. In this study, we investigated the signals that activate HSPCs during ehrlichiosis, a disease characterized by profound hematopoietic dysfunction in both humans and mice. In a mouse model of ehrlichiosis, we observed that infection-induced proliferation of bone marrow HSPCs was dependent on IFN-γ signaling and was partially dependent on MyD88. However, MyD88 was not required in HSPCs for their expansion during infection, because similar frequencies of MyD88-deficient and wild-type HSPCs proliferated in mixed bone marrow chimeric mice. MyD88-deficient mice exhibited low serum and bone marrow concentration of IFN-γ compared with wild-type mice. We next identified CD4 T cells as the primary cells producing IFN-γ in the bone marrow and demonstrated a nonredundant role for CD4-derived IFN-γ in increased HSPCs. Using mixed bone marrow chimeric mice, we identified a requirement for MyD88 in CD4 T cells for increased T-bet expression, optimal IFN-γ production, and CD4 T cell proliferation. Our data demonstrate an essential role for CD4 T cells in mediating HSPC activation in response to bacterial infection and illustrate a novel role for MyD88 signaling in CD4 T cells in this process. These findings further support the idea that IFN-γ production is essential for HSPC activation and hematopoietic responses to infection.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Maura
authors.initials: M
authors.lastname: Jones
authors.forename: Amanda
authors.initials: A
authors.lastname: McCabe
authors.forename: Gary M
authors.initials: GM
authors.lastname: Winslow
authors.forename: Dorina
authors.initials: D
authors.lastname: Avram
authors.forename: Katherine C
authors.initials: KC
authors.lastname: MacNamara
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D049109:Cell Proliferation; D004536:Ehrlichia / Q000276:immunology; D016873:Ehrlichiosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D007371:Interferon-gamma