| LP-BM5 murine retroviral infection induces murine AIDS (MAIDS), and is characterized by profound and broad immunosuppression of T- and B-cell responses. Adaptive immune response to LP-BM5 infection, including the pathogenic role of CD4+ T-cells and the protective role of CD8+ cytotoxic T-lymphocytes, has been previously explored. The Green Lab at Dartmouth has also previously described several mechanisms involved in the immunodeficiency of LP-BM5-induced disease, including Programmed Death 1 (PD-1), IL-10, and T-regulatory (Treg) cells. The role of innate immune mechanisms which mediate viral pathogenesis and/or modulate the host immune response to LP-BM5 retroviral infection had not been extensively explored and was the focus of study for this thesis work. We utilized various knockout murine strains to identify whether type I interferon signaling, TLR signaling pathways, or indoleamine 2-3, dioxygenase (IDO) enzymatic activity significantly contributed to LP-BM5 pathogenesis and disease progression. Immunomodulatory cellular subsets, including myeloid derived suppressor cells (MDSCs) and Tregs contribute to the immunosuppressive tumor microenvironment and are targets of immunotherapy. MDSCs and Tregs have been far less characterized in the context of retrovirus-associated immunosuppression. Monocytic (CD11b+Ly6G+/-/LoLy6C+) myeloid derived suppressor cells (M-MDSCs) expand following murine retroviral LP-BM5 infection and suppress ex vivo polyclonal T-cell and B-cell responses. We sorted heterogeneous LP-BM5-induced M-MDSCs into populations and subpopulations and revealed differential phenotypic and functional immunosuppressive M-MDSC subsets. Following in vivo adoptive transfer of natural Treg (nTreg) depleted CD4+ T-cells, and subsequent LP-BM5 retroviral infection, we identified altered phenotypic and functional M-MDSC subsets. Additionally, in vitro we identified a relationship between LP-BM5-derived MDSCs and Tregs. Collectively, these findings advance the knowledge of the innate immune response contributing to LP-BM5 pathogenesis and aspects of this work may provide insight into the role these molecules and cell types play in other retroviral systems. |
