B cells modulate systemic responses to Pneumocystis lung infection and 1 protect on - demand hematopoiesis via T cell - independent , innate 2 mechanism when type - I - IFN - signaling is absent

13 HIV infection results in a complex immunodeficiency due to loss of CD4 + T cells, impaired 14 type-I-IFN-responses and B cell-dysfunctions causing susceptibility to opportunistic infection 15 such as Pneumocystis pneumonia and unexplained comorbidities, including bone marrow 16 dysfunctions. Type-I-IFNs and B cells critically contribute to immunity to Pneumocystis lung 17 infection. We recently also identified B cells as supporters of on-demand hematopoiesis 18 following Pneumocystis infection that would otherwise be hampered due to systemic immune 19 effects initiated in the context of a defective type-I-IFN-system. While studying the role of type20 I-IFNs in immunity to Pneumocystis infection, we discovered that mice lacking both 21 lymphocytes and type-I-IFN-receptor (IFrag -/) developed progressive bone marrow failure 22 following infection, while lymphocyte-competent type-I-IFN-receptor-deficient mice (IFNAR -/) 23 showed transient bone marrow depression and extramedullary hematopoiesis. Lymphocyte24 reconstitution of lymphocyte-deficient IFrag -/mice pointed to B cells as a key player in bone 25 marrow protection. 26 Here we define how B cells protect on-demand hematopoiesis following Pneumocystis lung 27 infection in our model. We demonstrate that adoptive transfer of B cells into IFrag -/mice 28 protects early hematopoietic progenitor activity during systemic responses to Pneumocystis 29 infection thus promoting replenishment of depleted bone marrow cells. This activity is 30 independent of CD4 + T cell help and B cell-receptor-specificity, and does not require B cell 31 migration to the bone marrow. We furthermore show that B cells protect on-demand 32 hematopoiesis in part by induction of IL-10 and IL-27-mediated mechanisms. Thus our data 33 demonstrates an important immune-modulatory role of B cells during Pneumocystis lung 34 infection that complement the modulatory role of type-I-IFNs to prevent systemic complications. 35 on O cber 2, 2017 by gest http/iai.asm .rg/ D ow nladed fom