CMV infection results first in lytic replication which is controlled by CMV-specific T cells, followed by establishment of viral latency. CMV can sporadically reactivate in latently infected cells which is quickly controlled by CMV-specific T cells. CMV infection induces an atypical CD8 T cell response, characterized by the accumulation of a subset of highly protective CD8 T cells exhibiting an effector-like phenotype, a process termed "memory inflation". Their activated phenotype is caused by repetitive antigen encounter invoked by sporadic viral reactivation events. Although the half-life of inflationary T cells in mice is estimated to be around 6-12 weeks, the pool of inflationary T cell stabilizes at constant frequencies, implying continuous replenishment. A small subset of Tcf1+ inflationary MCMV-specific T cells, enriched in lymph nodes, feeds into the pool of inflationary CD8 T cells after antigen exposure.
Secretory glands are an attractive target tissue for viruses to persist and exploit mucosal secretions for dissemination, such as the salivary glands (SGs) in case of CMV. Murine CMV (MCMV) infection has revealed that virus-mediated MHC class I downregulation on infected epithelial cells renders the SG uniquely resistant to CD8 T cell mediated virus control. Instead, CD4 T cells are required to cease virus replication through the secretion of IFNγ and TNF. However, the question why and how long-lasting productive virus infection is maintained in the SG remains open. One important aspect that has so far not received enough attention is information about in situ tissue immunity in the SGs during MCMV infection, including spatial information about infection foci, distribution of infiltrating virus-specific T cells, sites of antigen recognition and IFNγ production. Using advanced microscopy methods in combination with mathematical modelling, we propose a scenario in which MCMV antigens in the SGs are sensed by virus-specific CD4 T cells only in an indirect manner, after remnants of previously infected cells have been engulfed by local antigen-presenting cells (APCs). This leads to locally confined IFNγ secretion, affording protection only in restricted areas. Eventual control occurs if local IFNg-concentrations allow sufficient accumulation of protected sites, and thus restriction of viral spread on an organ-wide range.