Cytomegalovirus (CMV) establishes a lifelong infection facilitated, in part, by circumventing immune defenses mediated by tumor necrosis factor (TNF)-family cytokines. An example of this is the mouse CMV (MCMV) m166 protein, which restricts expression of the TNF-related apoptosis-inducing ligand (TRAIL) death receptors, promoting early-phase replication. We show here that replication of an MCMV mutant lacking m166 is also severely attenuated during viral persistence in the salivary glands (SG). Depleting group I innate lymphoid cells (ILCs) or infecting Trail−/− mice completely restored persistent replication of this mutant. Group I ILCs are comprised of two subsets, conventional natural killer cells (cNK) and tissue-resident cells often referred to as innate lymphoid type I cells (ILC1). Using recently identified phenotypic markers to discriminate between these two cell types, their relative expression of TRAIL and gamma interferon (IFN-γ) was assessed during both early and persistent infection. ILC1 were found to be the major TRAIL expressers during both of these infection phases, with cNK expressing very little, indicating that it is ILC1 that curtail replication via TRAIL in the absence of m166-imposed countermeasures. Notably, despite high TRAIL expression by SG-resident ILC1, IFN-γ production by both ILC1 and cNK was minimal at this site of viral persistence. Together these results highlight TRAIL as a key ILC1-utilized effector molecule that can operate in defense against persistent infection at times when other innate control mechanisms may be muted and highlight the importance for the evolution of virus-employed countermeasures. IMPORTANCE Cytomegalovirus (a betaherpesvirus) is a master at manipulating immune responses to promote its lifelong persistence, a result of millions of years of coevolution with its host. Using a one-of-a-kind MCMV mutant unable to restrict expression of the TNF-related apoptosis-inducing ligand death receptors (TRAIL-DR), we show that TRAIL-DR signaling significantly restricts both early and persistent viral replication. Our results also reveal that these defenses are employed by TRAIL-expressing innate lymphoid type I cells (ILC1) but not conventional NK cells. Overall, our results are significant because they show the key importance of viral counterstrategies specifically neutralizing TRAIL effector functions mediated by a specific, tissue-resident subset of group I ILCs.
Robust CD4 T cell responses help to control chronic infection and restrict disease, but their specific requirements for resolving viral persistence remain poorly defined. During mouse cytomegalovirus (MCMV) infection, CD4 T cells recognizing an epitope derived from the viral M09 protein expand at late times of infection and display a unique phenotype compared to their conventional counterparts, including high IFNγ-production and low expression of the activated CD43 isoform. Ablating these late-rising CD4 T cells by mutating the MCMV M09 genomic epitope, or inducing them through vaccination, revealed their critical role in resolving persistent replication by overcoming IL-10 mediated immune suppression. Together, these data show that unique subsets of late-rising CD4 T cells are qualitatively superior in resolving chronic infection when compared to those that expand earlier, results that should be considered for vaccine development.
Conventional CD4 T cells typically expand and establish memory pools within the first few weeks of acute viral infection. However, cytomegalovirus (CMV) exhibits an extended persistent replication phase followed by lifelong latency, suggesting the induction, phenotype and/or function of protective memory CD4 T cells may differ. We show that during CMV infection in mice, CD4 T cells recognizing an epitope derived from the viral M09 protein develop long after conventional memory T cells have already formed. These cells are unique compared to their conventional memory counterparts; showing high IFNγ and IL-2 production at times of viral persistence. Ablating these CD4 T cells by mutating the M09 genomic epitope, or inducing them through vaccination, revealed them far superior at resolving persistent replication. RNAseq data reveal that these ‘late-rising’ and conventional CD4 T cells differ dramatically in their transcriptional signatures, and that M09 cells show a uniquely restricted T cell receptor repertoire. We believe these results may help instruct CMV vaccine and cellular immunotherapy approaches in people, and will also provide a blueprint for determining whether similar late-rising CD4 T cells exist in other chronic virus infections.
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) regulates cellular apoptosis and inflammation, and growing evidence indicates a key role in antiviral defense. Cytomegalovirus (CMV, a b-herpesvirus) establishes a lifelong persistent/latent infection that depends upon viral subversion of host innate and adaptive defenses. We have shown that both human and mouse CMV inhibit signaling by the TRAIL death receptors (DR) through the use of specific viral proteins. MCMV m166 blocks TRAIL-DR expression and promotes early viral replication by evading TRAIL-mediated natural killer (NK) cell defenses. After one week of systemic replication, MCMV spreads to the salivary glands (SG), the major mucosal organ responsible for horizontal transmission of the virus. We show that a MCMVΔm166 mutant replicates at lower absolute levels in the SG, but, surprisingly, persists for much longer times. Recent evidence suggests a role of type 1 Innate Lymphoid cells (ILC1) in control/clearance of MCMV. We investigated the role of the 2 main ILC1 populations (conventional and tissue resident (tr) NK cells) in controlling MCMV SG persistence. Depleting ILC1 prior to infection, or infection of TRAIL−/− mice, restored MCMVΔm166 SG replication to normal levels. In addition, SG trNK cells display a unique phenotype and express high levels of TRAIL during MCMV infection when compared to their conventional counterparts. Together our data reveal a key role for m166 inhibition of TRAIL-DR expression in promoting viral persistence by blocking ILC1 effector functions mediated by TRAIL, highlighting this TNF-family cytokine as an important factor regulating innate defenses in mucosal tissues.
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