Abstract
Cytomegalovirus (CMV) infection elicits a strong T-cell immune response, which increases further during aging in a process termed “memory inflation.” CMV downregulates the expression of HLA-A and HLA-B on the surface of infected cells to limit presentation of viral peptides to T-cells although HLA-C is relatively spared as it also engages with inhibitory killer immunoglobulin receptor receptors and therefore reduces lysis by natural killer cells. We investigated the magnitude and functional properties of CMV-specific CD8+ T-cells specific for 10 peptides restricted by HLA-C in a cohort of 53 donors between the age of 23 and 91 years. This was achieved via peptide stimulation of PBMCs followed by multicolor flow cytometry. Three peptides, derived from proteins generated in the immediate-early period of viral replication and restricted by HLA-Cw*0702, elicited strong immune responses, which increased substantially with age such that the average aggregate response represented 37% of the CD8+ T-cell pool within donors above 70 years of age. Remarkably, a single response represented 70% of the total CD8+ T-cell pool within a 91-year-old donor. HLA-Cw*0702-restricted CD8+ T-cell responses were immunodominant over HLA-A and HLA-B-restricted CMV-specific responses and did not show features of exhaustion such as PD-1 or CD39 expression. Indeed, such CTL exhibit a polyfunctional cytokine profile with co-expression of IFN-γ and TNF-α and a strong cytotoxic phenotype with intracellular expression of perforin and granzymeB. Functionally, HLA-Cw*0702-restricted CTL show exceptionally high avidity for cognate peptide-HLA and demonstrate very early and efficient recognition of virally infected cells. These observations indicate that CD8+ T-cells restricted by HLA-C play an important role in the control of persistent CMV infection and could represent a novel opportunity for CD8+ T-cell therapy of viral infection within immunosuppressed patients. In addition, the findings provide further evidence for the importance of HLA-C-restricted T-cells in the control of chronic viral infection.
Highlights
Human cytomegalovirus (CMV) is a β-herpesvirus with a seroprevalence of 60–90% depending on geographical location
Virus-specific CD8+ T-cells restricted by HLA-C have received considerably less investigation than responses restricted by HLA-A or HLA-B
We have shown that CD8+ T-cells specific for peptides derived from proteins expressed in the IE phase of CMV replication and restricted by HLA-Cw*0702 elicit potent CD8+ T-cell responses
Summary
Human cytomegalovirus (CMV) is a β-herpesvirus with a seroprevalence of 60–90% depending on geographical location. HLA-C is the major ligand for inhibitory killer immunoglobulin receptors on natural killer cells (NK cells) and as such exhibits a dual role between NK and T-cell recognition [15, 18]. This observation is likely to explain why virally encoded immune evasion proteins which downregulate the expression of most HLA class I proteins have evolved to allow relative retention of HLA-C at the cell surface to prevent NK recognition of the infected cell. HLA-C-restricted T-cells are important in hepatitis B infection where HLA-Cw0801restricted recognition of Env171180 is associated with viral clearance [23]
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