Periodic Reporting for period 1 - MISTRO (Identification of the cellular sites of cytomegalovirus latency that contribute to the induction of inflationary CD8 T cell memory against the virus.)
Reporting period: 2018-04-01 to 2020-03-31
(1) The data provide the first formal demonstration that cytomegaloviruses establish latency in PDGFR+ mesenchymal stromal cells, a cell type previously known to be permissive to lytic, but not latent CMV infection, thus arguing against the field’s paradigmatic view that CMV induces lytic and latent infections in distinct cell types or differentiation states.
(2) The data characterize the distribution of latent CMV genomes in stromal cell subsets of lymphoid tissues with unprecedented depth and describe Tcf21+ splenic red pulp stromal cells as the primary site of CMV latency in lymphoid organs.
The findings (1-2) extend our understanding of the mechanisms of viral latency and are anticipated to prompt in-depth mechanistic studies focusing on identification of candidate molecular pathways harnessing the ability of CMV to reactivate in immune suppressed patients.
(3) The data establish that viral antigens that sustain memory inflation must be processed by latently infected stromal cells, whereas antigen processing by professional antigen presenting cells of hematopoietic origin cells is not sufficient.
(4) The data rule out that memory inflation is driven by the stromal cell population with the highest viral genomic load in lymphoid tissues, the splenic red pulp cells, but rather is sustained through redundant contribution of various latently infected cell subsets.
The findings (3-4) may lay basis for future development of improved vaccination vectors that directly target stromal cells.