Cytomegalovirus infection and progressive differentiation of effector-memory T cells

Abstract

Primary cytomegalovirus (CMV) infection leads to strong innate and adaptive immune responses against the virus, which prevents serious disease. However, CMV infection can cause serious morbidity and mortality in individuals who are immunocompromised. The adaptive immune response to CMV is characterized by large populations of effector-memory (EM) T cells that are maintained lifelong, a process termed memory inflation. Recent findings indicate that infection with CMV leads to continuous differentiation of CMV-specific EM-like T cells and that high-dose infection accelerates this progression. Whether measures that counteract CMV infection, such as anti-viral drugs, targeting of latently infected cells, adoptive transfer of CMV-specific T cells, and vaccination strategies, are able to impact the progressive differentiation of CMV-specific EM-like cells is discussed.

Keywords: Cytomegalovirus; T cell differentiation; memory CD8 T cell; memory inflation.

Figure 1.. Progressive differentiation of cytomegalovirus (CMV)-specific effector-memory (EM) CD8 ⁺ T cells and its relation to the initial viral inoculum.

C57BL/6 mice were infected intraperitoneally with a low (10 ³ plaque-forming units, or PFU) or a high (10 ⁵ PFU) dose of mouse CMV (MCMV)-Smith. Inflationary IE3-specific CD8 ⁺ T cells in blood were detected with major histocompatibility complex (MHC) class I tetramer (Tet) and stained for the cell surface markers CD62L, KLRG1, CD27, and CD44, which allow discrimination between central-memory (CM) and EM-like T cells at days 8, 90, and 200 after infection. ( a) IE3-specific cells were gated (Tet ⁺) and an equally down-sampled number of cells per sample was analyzed by Cytosplore. Single-marker expression of IE3-specific CD8 ⁺ T cells is shown as Approximated t-distributed Stochastic Neighbor Embedding (A-tSNE) scatterplots to visualize the intensity of the markers. ( b) A-tSNE plot depicts the pooled phenotypical data of the cell surface markers visualized as cell density clusters of the IE3-specific CD8 ⁺ T cells of low- and high-dose MCMV-infected mice for day 8, 90, and 200 time points after infection. In the A-tSNE plot, the differentiation path from the CM and EM phenotype is specified. The black curved line indicates the ongoing shift toward a higher advanced EM phenotype. Clusters showing different points in the differentiation path were selected and indicated by dashed line boxes. The percentage of IE3-specific CD8 ⁺ T cells in the selected clusters was determined and displayed in the corresponding bar graphs for each time point and viral inoculum.