Regulation of Anti-viral Immunity by Dendritic Cells and Natural Killer Cells

4-1BB and its ligand, 4-1BBL, are costimulatory members of the tumor necrosis factor receptor (TNFR)/TNF family. The 4-1BB/4-1BBL pathway has been shown to potently enhance T cell responses in models of viral infection and cancer, thereby identifying this pathway as a target for immunotherapy. In addition to T cells, 4-1BB is expressed on dendritic cells (DCs), which also express 4-1BBL. The precise nature of 4-1BB/4-1BBL expression on DCs is not known and the endogenous function of 4-1BB/4-1BBL on this cell type has remained largely elusive. Here, I show that LPS-activated bone marrow-derived DCs express both 4-1BB and 4-1BBL, and that these molecules constitutively interact on DCs. Survival, upregulation of key costimulatory molecules, cytokine/chemokine production, antigen presentation, and the ability of DCs to generate primary influenza-specific CD8 T cell responses were normal in the absence of 4-1BB and/or 4-1BBL on DCs. Thus, the biological implications of 4-1BB/4-1BBL interactions on DCs remain to be elucidated. It was previously demonstrated in the Watts lab that the 4-1BB pathway on T cells becomes desensitized during persistent infection with lymphocytic choriomeningitis virus (LCMV) clone 13 through loss of the signaling adapter TRAF1. In the course of these studies, it was found that 2 months following LCMV clone 13 infection, a time point at which virus is largely cleared from the spleen and other organs, C57BL/6 mice showed dramatic splenic atrophy. Here, I show that this atrophy persists for up to 10 months following initial infection and that it does not occur with the acutely infecting strain, LCMV Armstrong. I go on to show that splenic atrophy is mediated in part by natural killer (NK) cells, and implicate NKG2D-MULT1 interactions as contributing to late-stage B cell depletion. Compared to isotype control antibody treatment, type I interferon receptor 1 (IFNAR1) blocking antibody treatment at the onset of splenic atrophy increased the proportion of NK cells in the spleen, and was correlated with exacerbated splenic atrophy. Lastly, splenic atrophy following LCMV clone 13 infection was associated with delayed clearance of a bacterial pathogen. These findings implicate NK cells in the pathophysiological mechanisms underlying splenic atrophy following viral infection.Ph.D.2017-06-30 00:00:0