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Massive Load of Functional Effector CD4⁺ and CD8⁺ T Cells against Cytomegalovirus in Very Old Subjects¹

Rosanna Vescovini^*, Claudia Biasini^*, Francesco F. Fagnoni, Anna Rita Telera^*, Luca Zanlari^*, Mario Pedrazzoni^*, Laura Bucci, Daniela Monti, Maria Cristina Medici, Carlo Chezzi, Claudio Franceschi^¶ and Paolo Sansoni^2,*

^* 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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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