Differential localization and kinetics of antiviral CD8 T cell responses to chronic and acute murine norovirus infections from initiation onwards

Abstract

Abstract Recent global events have highlighted the need to better understand mucosal antiviral immunity. Murine Norovirus (MNV) is small non-enveloped positive sense RNA virus that can be used as a model of intestinal viral infection. In this work we use two highly related MNV strains with distinct biological behaviors; CR6 establishes chronic colonic infection, while CW3 establishes systemic infection initiated in the small intestine and is cleared by day 8, correlating with the peak of cell-mediated adaptive immunity. Using flow cytometry and quantitative immunofluorescent microscopy (QIM) of transgenic P14 CD8 T cells specific to recombinant CR6gp33 and CW3gp33, we characterized CD8 T cell responses to CR6 and CW3 from initiation to clearance of CW3. Our data indicate that initiation of CD8 T cell division in response to CR6 infection is delayed, less robust, and largely limited to the mesenteric lymph nodes (MLNs) with less splenic division compared to CW3 infection. Further, the biogeography of P14 T cell priming differs, as early T cell expansion was restricted to distinct nodes of the MLN complex. These early differences propagate out to the time of CW3 clearance. By day 8, there is differential localization of P14 cells in the GI tract to the site of highest viral load and a larger systemic population of P14 cells following CW3 infection. Infection of MLN-deficient mice revealed a critical role for MLN surveillance in targeting P14 T cells to the GI tract following CR6 infection while the spleen plays a compensatory role in response to CW3. These results show how distinct infectious locations of a continuous mucosal surface influence the responses of antiviral CD8 T cells without confounding effects of antigenicity. This work is supported by the Canadian Institutes for Health Research (CIHR) and a UBC 4 Year Fellowship awarded to Blair K Hardman