Differential phenotypes and localization of CD8 T cell responses to acute and chronic viral infections

Abstract

Abstract Norovirus is the most common viral cause of gastroenteritis globally. Most infections are either acute, symptomatic, and rapidly cleared or persist asymptomatically. However, the mechanisms underlying these outcomes are unknown. MNV-CW3 and -CR6 are murine noroviruses which demonstrate immune correlates of acute and chronic infection respectively. This research interrogates the mechanisms underlying strain-specific differential antiviral CD8 T cell responses to acute or chronic MNV. At days 3, 4, 5 and 8 post-infection, the phenotype and quantity of adoptively transferred MNV specific CD8 T cells in the spleen, mesenteric lymph node (MLN), and intestines are analyzed by flow cytometry. Concurrently, fluorescent microscopy is used to determine the biogeographical distribution of antiviral CD8 T cells throughout the intestine. Flow cytometry shows activated MNV-specific CD8 T cells first accumulate in the MLN following oral infection with either virus suggesting this is the site of immune activation though CR6 infection results in a delayed, reduced CD8 T cell response as shown by CFSE dilution. Supporting the MLN as a primary initiation site of the antiviral CD8 T cell response, prevention of T cell egress from activation sites by FTY720 treatment enriches activated CD8 T cells in the MLN in CW3 infections with a concurrent decrease in the spleen. Furthermore, by day 8 post-infection CD8 T cell populations are skewed to memory precursors or short-lived effectors in CW3 and CR6, respectively. These data suggest these highly related viral strains may induce activation of distinct populations of, or pathways in, APC populations with long-lasting effects on CD8 T cell function and the outcome of infection.