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* Department of Internal Medicine and Biomedical Sciences, University of Parma, Parma, Italy;
Laboratory of Experimental Oncology, Scientific Institute of Pavia Fondazione S. Maugeri Clinica del Lavoro e della Riabilitazione, Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Italy;
Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy;
Section of Microbiology, Department of Pathology and Laboratory Medicine, University of Parma, Parma, Italy;
¶ Department of Experimental Pathology, University of Bologna and Interdepartmental Centre for Studies on Biophysics, Bioinformatics and Biocomplexity L. Galvani, Bologna, Italy
A progressive, systemic, and low-grade proinflammatory status is one of the major characteristics of immunosenescence. Emerging data suggest a possible contribution of CMV, known to chronically infect a large proportion of humans, lifelong from newborns to centenarians. To test this hypothesis, we evaluated functional T cell responses to two CMV immunogenic proteins, pp65 and IE-1, in 65 chronically infected subjects aged 25–100 years. PBMC were stimulated with mixtures of peptides spanning the entire sequence of both proteins, and Ag specificity and magnitude of intracellular IFN-
- and TNF-
-positive cells were then analyzed within both CD4+ and CD8+ T cells. Results indicate that pp65 and, to a lesser extent, IE-1 constitute major Ags against which aged people target functionally efficient T cell effector responses with massive production of Th1 cytokines and exhibition of CD107a degranulation marker. As a result, the production of IFN- induced in T cells by both Ags was seven to eight times greater in very old than in young subjects. The comparative analysis of pp65-specific responses in these very long-term carriers revealed a reciprocal relationship between CD4+ and CD8+ producing IFN- in the same individuals. These results indicate that CMV represents an important pathogen responsible for a strong immune activation in human aging. Such a remarkable burden of effector CD4+ and CD8+ T cells may be necessary to protect the elderly from CMV endogenous reactivation, but can turn detrimental by giving a substantial contribution to the proinflammatory status that accompanies the main age-related diseases.
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1 This work was supported by a grant (to P.S. and D.M.) from Ministero dell’Università e della Ricerca (PRIN2004, ex 40%) "Invecchiamento e Sistema Immunitario nell’uomo: ruolo della stimolazione antigenica cronica" and by a grant (to P.S.) from the "Fondazione Cassa di Risparmio di Parma e Piacenza." This work was also supported by the Emilia-Romagna Region and Fondi Strutturali Obiettivo 2; Italian Ministry of Health Project "Markers genetici di sindrome coronaria acuta e valutazione della l-arginina nella prevenzione di eventi ischemici" (to D.M. and C.F.); European Union Project "ZINCAGE" 6th Framework Project, Contract FOOD-CT-2003-506850 (to D.M.); and University of Bologna Ricerca Fondamentale Orientata (RFO ex 60%) 2005 and Roberto Pallotti Legacy for Cancer Research Grants (to C.F.).
2 Address correspondence and reprint requests to Dr. Paolo Sansoni, Department of Internal Medicine and Biomedical Sciences, University of Parma, via Gramsci 14, 43100 Parma, Italy. E-mail address: paolo.sansoni{at}unipr.it
3 Abbreviation used in this paper: IE-1, immediate early 1 gene product.
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