Myeloid-Derived suppressor cells in murine retrovirus-induced AIDS: inhibition of the T-cell and B-cell responsiveness that define the immunodeficiency (170.7)

Abstract

Abstract Myeloid-derived suppressor cells (MDSCs) have been characterized in several tumor settings however, they have been less well studied in response to infectious disease processes, in particular against retroviruses that induce immunodeficiency. Here we demonstrate for the first time the development of a highly immunosuppressive MDSC population that is dependent on LP-BM5 retrovirus infection, which causes murine acquired immunodeficiency. This MDSC population is CD11b+, Gr-1+, Ly6C+ , exhibits profound inhibition of immune responsiveness by a cell-dose and substantially iNOS-dependent mechanism that is independent of arginase activity, PD-1/PD-L1 expression, and IL-10; and the degree of immunosuppression parallels the extent of disease in differentially LP-BM5 susceptible w.t. vs. knock-out mouse strains. Not only T-cell, but also interestingly B-cell host responses, were suppressed by these MDSCs. The direct immunosuppression of B cell responses was confirmed by use of: purified B responder cells, multiple B-cell specific stimuli, and independent assays measuring B-cell expansion. This suppressive MDSC subset is positive for proviral LP-BM5 RNA, albeit at a significantly lower level than LP-BM5 infected non-fractionated spleen cells. These results, including the strong, direct MDSC inhibition of B-cell responsiveness, are novel for murine retrovirus-induced immunosuppression, and support a possible pathogenic effector role for these retrovirus-induced MDSCs.