Differentiation and Protective Capacity of Virus-Specific CD8+ T Cells Suggest Murine Norovirus Persistence in an Immune-Privileged Enteric Niche

Abstract

SUMMARY Noroviruses can establish chronic infections with active viral shedding in healthy humans but whether persistence is associated with adaptive immune dysfunction is unknown. We used genetically engineered strains of mouse norovirus (MNV) to investigate CD8+ T cell differentiation during chronic infection. We found that chronic infection drove MNV-specific tissue-resident memory (Trm) CD8+ T cells to a differentiation state resembling inflationary effector responses against latent cytomegalovirus with only limited evidence of exhaustion. These MNV-specific Trm cells remained highly functional yet appeared ignorant of ongoing viral replication. Pre-existing MNV-specific Trm cells provided partial protection against chronic infection but largely ceased to detect virus within 72 hours of challenge, demonstrating rapid sequestration of viral replication away from T cells. Our studies revealed a strategy of immune evasion by MNV via the induction of a CD8+ T cell program normally reserved for latent pathogens and persistence in an immune-privileged enteric niche.

The Dual Tropism of Noroviruses

“…These data suggest tuft cells are an immune-privileged cell type in the intestine. This is consistent with previous work demonstrating that gutresident T cells against MNV-CR6 are functional but ignorant of viral replication during the persistent phase of infection (33). More information is needed to determine the mechanism by which maintenance of a pool of infected tuft cells occurs in an environment of intestinal villi that are continuously renewed.…”

The (gradual) rise of memory inflation

“…These features of CD8 + T‐cell responses have been observed in other infection settings such as chronic norovirus infection in mice,41 and some extreme responses to Epstein Barr Virus (EBV infection) in humans 42. Such responses, as well as those induced by adenoviral vectored vaccines in humans could be called “inflation‐like”.…”

“…Although this is typically considered an acute infection, chronic infections can also be established with specific viral strains. In one of these, a persistence of virus is associated with emergence of an “inflationary” as opposed to an exhausted CD8 + T‐cell phenotype in the gut 41. It is not clear why the virus is able to trigger long‐term functional T‐cell expansion like CMV, without the same virologic strategy, but fundamentally some mismatch between where virus is presented to the immune system and the cells in which it is successfully replicating is postulated (ie, T cell “ignorance”).…”

The Role of Interferon in Persistent Viral Infection: Insights from Murine Norovirus

“…Furthermore, CW3 elicits a more robust expansion of MNV-specific CTLs in the intestine and spleen than CR6 [62]. However, mutation of a single amino acid difference in the CR6 CTL epitope (F525Y) results in robust expansion of MNV-specific CTLs, but does not prevent CR6 persistence [63]. Additionally, there is no evidence of clonal deletion or non-responsiveness of CR6-specific CTLs, as is seen in persistent LCMV infection [62,63].…”

“…However, mutation of a single amino acid difference in the CR6 CTL epitope (F525Y) results in robust expansion of MNV-specific CTLs, but does not prevent CR6 persistence [63]. Additionally, there is no evidence of clonal deletion or non-responsiveness of CR6-specific CTLs, as is seen in persistent LCMV infection [62,63]. Instead, CR6-specific CTLs remain functional but do not “see” continuous viral replication in the intestine, and the CTL transcriptome during CR6 persistence resembles the murine cytomegalovirus (MCMV) CTL transcriptome during MCMV latency [63].…”