title: B cells modulate systemic responses to Pneumocystis murina lung infection and protect on-demand hematopoiesis via T cell-independent innate mechanisms when type I interferon signaling is absent.
abstract: HIV infection results in a complex immunodeficiency due to loss of CD4(+) T cells, impaired type I interferon (IFN) responses, and B cell dysfunctions causing susceptibility to opportunistic infections such as Pneumocystis murina pneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity to Pneumocystis lung infection. We recently also identified B cells as supporters of on-demand hematopoiesis following Pneumocystis infection that would otherwise be hampered due to systemic immune effects initiated in the context of a defective type I IFN system. While studying the role of type I IFNs in immunity to Pneumocystis infection, we discovered that mice lacking both lymphocytes and type I IFN receptor (IFrag(-/-)) developed progressive bone marrow failure following infection, while lymphocyte-competent type I IFN receptor-deficient mice (IFNAR(-/-)) showed transient bone marrow depression and extramedullary hematopoiesis. Lymphocyte reconstitution of lymphocyte-deficient IFrag(-/-) mice pointed to B cells as a key player in bone marrow protection. Here we define how B cells protect on-demand hematopoiesis following Pneumocystis lung infection in our model. We demonstrate that adoptive transfer of B cells into IFrag(-/-) mice protects early hematopoietic progenitor activity during systemic responses to Pneumocystis infection, thus promoting replenishment of depleted bone marrow cells. This activity is independent of CD4(+) T cell help and B cell receptor specificity and does not require B cell migration to bone marrow. Furthermore, we show that B cells protect on-demand hematopoiesis in part by induction of interleukin-10 (IL-10)- and IL-27-mediated mechanisms. Thus, our data demonstrate an important immune modulatory role of B cells during Pneumocystis lung infection that complement the modulatory role of type I IFNs to prevent systemic complications.
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA.
authors.forename: Teri R
authors.initials: TR
authors.lastname: Hoyt
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Dobrinen
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Kochetkova
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA natascha.meissner@montana.edu.
authors.forename: Nicole
authors.initials: N
authors.lastname: Meissner
mesh_terms: D019264:Adoptive Transfer; D000741:Anemia, Aplastic; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006410:Hematopoiesis / Q000276:immunology*; D006457:Hemoglobinuria, Paroxysmal / Q000276:immunology / Q000382:microbiology; D007370:Interferon Type I / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D011010:Pneumocystis / Q000276:immunology*; D011020:Pneumonia, Pneumocystis / Q000276:immunology*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics*
chemical_list: C556062:IL10 protein, mouse; C486767:Il27 protein, mouse; D007370:Interferon Type I; D007378:Interleukins; D016753:Interleukin-10; D053633:Receptor, Interferon alpha-beta