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 asPneumocystis murinapneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity toPneumocystislung infection. We recently also identified B cells as supporters of on-demand hematopoiesis followingPneumocystisinfection 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 toPneumocystisinfection, 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 followingPneumocystis lung infection in our model. We demonstrate that adoptive transfer of B cells into IFrag−/−mice protects early hematopoietic progenitor activity during systemic responses toPneumocystisinfection, 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 duringPneumocystislung infection that complement the modulatory role of type I IFNs to prevent systemic complications.