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

Journal of Immunology - Tập 179 Số 6 - Trang 4283-4291 - 2007
Rosanna Vescovini1, Claudia Biasini1, Francesco Fagnoni2, Anna Rita Telera1, Luca Zanlari1, Mario Pedrazzoni1, Laura Bucci3, Daniela Monti3, Maria Cristina Medici4, Carlo Chezzi4, Claudio Franceschi5, Paolo Sansoni1
1Department of Internal Medicine and Biomedical Sciences, University of Parma, Parma, Italy
2†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;
3Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy
4Section of Microbiology, Department of Pathology and Laboratory Medicine, University of Parma, Parma, Italy
5¶Department of Experimental Pathology, University of Bologna and Interdepartmental Centre for Studies on Biophysics, Bioinformatics and Biocomplexity L. Galvani, Bologna, Italy

Tóm tắt

Abstract 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-γ- and TNF-α-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-γ 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-γ 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.

Từ khóa


Tài liệu tham khảo

Fagnoni, F. F., R. Vescovini, M. Mazzola, G. Bologna, E. Nigro, G. Lavagetto, C. Franceschi, M. Passeri, P. Sansoni. 1996. Expansion of cytotoxic CD8+ CD28− T cells in healthy ageing people, including centenarians. Immunology 88: 501-507.

Franceschi, C., S. Valensin, F. F. Fagnoni, C. Barbi, M. Bonafe. 1999. Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load. Exp. Gerontol. 34: 911-921.

Fagnoni, F. F., R. Vescovini, G. Passeri, G. Bologna, M. Pedrazzoni, G. Lavagetto, A. Casti, C. Franceschi, M. Passeri, P. Sansoni. 2000. Shortage of circulating naive CD8+ T cells provides new insights on immunodeficiency in aging. Blood 95: 2860-2868.

Zanni, F., R. Vescovini, C. Biasini, F. F. Fagnoni, L. Zanlari, A. Telera, P. di Pede, G. Passeri, M. Pedrazzoni, M. Passeri, et al 2003. Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+ T cells in humans: a contribution to understand the relationship between inflammation and immunosenescence. Exp. Gerontol. 38: 981-987.

Gerli, R., D. Monti, O. Bistoni, A. M. Mazzone, G. Peri, A. Cossarizza, M. Di Gioacchino, M. E. Cesarotti, A. Doni, A. Mantovani, et al 2000. Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech. Ageing Dev. 121: 37-46.

Bruunsgaard, H., K. Andersen-Ranberg, J. B. Hjelmborg, B. K. Pedersen, B. Jeune. 2003. Elevated levels of tumor necrosis factor α and mortality in centenarians. Am. J. Med. 115: 278-283.

Franceschi, C., M. Bonafe, S. Valensin, F. Olivieri, M. De Luca, E. Ottaviani, G. De Benedictis. 2000. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann. NY Acad. Sci. 908: 244-254.

Sylwester, A. W., B. L. Mitchell, J. B. Edgar, C. Taormina, C. Pelte, F. Ruchti, P. R. Sleath, K. H. Grabstein, N. A. Hosken, F. Kern, et al 2005. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202: 673-685.

Pawelec, G., A. Akbar, C. Caruso, R. Solana, B. Grubeck-Loebenstein, A. Wikby. 2005. Human immunosenescence: is it infectious?. Immunol. Rev. 205: 257-268.

Akbar, A. N., J. M. Fletcher. 2005. Memory T cell homeostasis and senescence during aging. Curr. Opin. Immunol. 17: 480-485.

Khan, N., N. Shariff, M. Cobbold, R. Bruton, J. A. Ainsworth, A. J. Sinclair, L. Nayak, P. A. Moss. 2002. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 169: 1984-1992.

Ouyang, Q., W. M. Wagner, A. Wikby, S. Walter, G. Aubert, A. I. Dodi, P. Travers, G. Pawelec. 2003. Large numbers of dysfunctional CD8+ T lymphocytes bearing receptors for a single dominant CMV epitope in the very old. J. Clin. Immunol. 23: 247-257.

Vescovini, R., A. Telera, F. F. Fagnoni, C. Biasini, M. C. Medici, P. Valcavi, P. di Pede, G. Lucchini, L. Zanlari, G. Passeri, et al 2004. Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. Exp. Gerontol. 39: 1233-1243.

Khan, N., A. Hislop, N. Gudgeon, M. Cobbold, R. Khanna, L. Nayak, A. B. Rickinson, P. A. Moss. 2004. Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J. Immunol. 173: 7481-7489.

Ouyang, Q., W. M. Wagner, W. Zheng, A. Wikby, E. J. Remarque, G. Pawelec. 2004. Dysfunctional CMV-specific CD8+ T cells accumulate in the elderly. Exp. Gerontol. 39: 607-613.

Almanzar, G., S. Schwaiger, B. Jenewein, M. Keller, D. Herndler-Brandstetter, R. Wurzner, D. Schonitzer, B. Grubeck-Loebenstein. 2005. Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J. Virol. 79: 3675-3683.

Fletcher, J. M., M. Vukmanovic-Stejic, P. J. Dunne, K. E. Birch, J. E. Cook, S. E. Jackson, M. Salmon, M. H. Rustin, A. N. Akbar. 2005. Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J. Immunol. 175: 8218-8225.

Pourgheysari, B., N. Khan, D. Best, R. Bruton, L. Nayak, P. A. H. Moss. 2007. The cytomegalovirus-specific CD4+ T cell response expands with age and markedly alters the CD4+ T cell repertoire. J. Virol. 81: 7759-7765.

Hoffmeister, B., F. Kiecker, L. Tesfa, H. D. Volk, L. J. Picker, F. Kern. 2003. Mapping T cell epitopes by flow cytometry. Methods 29: 270-281.

Betts, M. R., J. M. Brenchley, D. A. Price, S. C. De Rosa, D. C. Douek, M. Roederer, R. A. Koup. 2003. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J. Immunol. Methods 281: 65-78.

Rubio, V., T. B. Stuge, N. Singh, M. R. Betts, J. S. Weber, M. Roederer, P. P. Lee. 2003. Ex vivo identification, isolation and analysis of tumor-cytolytic T cells. Nat. Med. 9: 1377-1382.

Franceschi, C., S. Valensin, M. Bonafe, G. Paolisso, A. I. Yashin, D. Monti, G. De Benedictis. 2000. The network and the remodeling theories of aging: historical background and new perspectives. Exp. Gerontol. 35: 879-896.

De Martinis, M., C. Franceschi, D. Monti, L. Ginaldi. 2005. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett. 579: 2035-2039.

Franceschi, C., M. Capri, D. Monti, S. Giunta, F. Olivieri, F. Sevini, M. P. Panourgia, L. Invidia, L. Celani, M. Scurti, et al 2007. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128: 92-105.

Schmaltz, H. N., L. P. Fried, Q. L. Xue, J. Walston, S. X. Leng, R. D. Semba. 2005. Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. J. Am. Geriatr. Soc. 53: 747-754.

Dunn, H. S., D. J. Haney, S. A. Ghanekar, P. Stepick-Biek, D. B. Lewis, H. T. Maecker. 2002. Dynamics of CD4 and CD8 T cell responses to cytomegalovirus in healthy human donors. J. Infect. Dis. 186: 15-22.

Kern, F., T. Bunde, N. Faulhaber, F. Kiecker, E. Khatamzas, I. M. Rudawski, A. Pruss, J. W. Gratama, R. Volkmer-Engert, R. Ewert, et al 2002. Cytomegalovirus (CMV) phosphoprotein 65 makes a large contribution to shaping the T cell repertoire in CMV-exposed individuals. J. Infect. Dis. 185: 1709-1716.

Sester, M., U. Sester, B. Gartner, B. Kubuschok, M. Girndt, A. Meyerhans, H. Kohler. 2002. Sustained high frequencies of specific CD4 T cells restricted to a single persistent virus. J. Virol. 8: 3748-3755.

Weekes, M. P., M. R. Wills, J. G. Sissons, A. J. Carmichael. 2004. Long-term stable expanded human CD4+ T cell clones specific for human cytomegalovirus are distributed in both CD45RAhigh and CD45ROhigh populations. J. Immunol. 173: 5843-5851.

Appay, V., J. J. Zaunders, L. Papagno, J. Sutton, A. Jaramillo, A. Waters, P. Easterbrook, P. Grey, D. Smith, A. J. McMichael, et al 2002. Characterization of CD4+ CTLs ex vivo. J. Immunol. 168: 5954-5958.

van Leeuwen, E. M., E. B. Remmerswaal, M. T. Vossen, A. T. Rowshani, P. M. Wertheim-van Dillen, R. A. van Lier, I. J. ten Berge. 2004. Emergence of a CD4+CD28− granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. J. Immunol. 173: 1834-1841.

van Leeuwen, E. M., E. B. Remmerswaal, M. H. Heemskerk, I. J. ten Berge, R. A. van Lier. 2006. Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection. Blood 108: 3121-3127.

Hegde, N. R., C. Dunn, D. M. Lewinsohn, M. A. Jarvis, J. A. Nelson, D. C. Johnson. 2005. Endogenous human cytomegalovirus gB is presented efficiently by MHC class II molecules to CD4+ CTL. J. Exp. Med. 202: 1109-1119.

Adhikary, D., U. Behrends, A. Moosmann, K. Witter, G. W. Bornkamm, J. Mautner. 2006. Control of Epstein-Barr virus infection in vitro by T helper cells specific for virion glycoproteins. J. Exp. Med. 203: 995-1006.

Heller, K. N., C. Gurer, C. Munz. 2006. Virus-specific CD4+ T cells: ready for direct attack. J. Exp. Med. 203: 805-808.

Casazza, J. P., M. R. Betts, D. A. Price, M. L. Precopio, L. E. Ruff, J. M. Brenchley, B. J. Hill, M. Roederer, D. C. Douek, R. A. Koup. 2006. Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation. J. Exp. Med. 203: 2865-2877.

Kern, F., I. P. Surel, N. Faulhaber, C. Frommel, J. Schneider-Mergener, C. Schonemann, P. Reinke, H. D. Volk. 1999. Target structures of the CD8+-T-cell response to human cytomegalovirus: the 72-kilodalton major immediate-early protein revisited. J. Virol. 73: 8179-8184.

Kern, F., N. Faulhaber, C. Frommel, E. Khatamzas, S. Prosch, C. Schonemann, I. Kretzschmar, R. Volkmer-Engert, H. D. Volk, P. Reinke. 2000. Analysis of CD8 T cell reactivity to cytomegalovirus using protein-spanning pools of overlapping pentadecapeptides. Eur. J. Immunol. 30: 1676-1682.

Khan, N., M. Cobbold, R. Keenan, P. A. Moss. 2001. Comparative analysis of CD8+ T cell responses against human cytomegalovirus proteins pp65 and immediate early 1 shows similarities in precursor frequency, oligoclonality, and phenotype. J. Infect. Dis. 185: 1025-1034.

Bunde, T., A. Kirchner, B. Hoffmeister, D. Habedank, R. Hetzer, G. Cherepnev, S. Proesch, P. Reinke, H. D. Volk, H. Lehmkuhl, F. Kern. 2005. Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J. Exp. Med. 201: 1031-1036.

Lacey, S. F., J. Martinez, G. Gallez-Hawkins, L. Thao, J. Longmate, W. Haq, R. Spielberger, S. J. Forman, J. A. Zaia, D. J. Diamond. 2005. Simultaneous reconstitution of multiple cytomegalovirus-specific CD8+ cell populations with divergent functionality in hematopoietic stem-cell transplant recipients. J. Infect. Dis. 191: 977-984.

Lacey, S. F., C. La Rosa, W. Zhou, M. C. Sharma, J. Martinez, A. Krishnan, G. Gallez-Hawkins, L. Thao, J. Longmate, R. Spielberger, et al 2006. Functional comparison of T cells recognizing cytomegalovirus pp65 and intermediate-early antigen polypeptides in hematopoietic stem-cell transplant and solid organ transplant recipients. J. Infect. Dis. 194: 1410-1421.

Appay, V., P. R. Dunbar, M. Callan, P. Klenerman, G. M. Gillespie, L. Papagno, G. S. Ogg, A. King, F. Lechner, C. A. Spina, et al 2002. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med. 8: 379-385.

Kalams, S. A., B. D. Walker. 1998. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J. Exp. Med. 188: 2199-2204.

Ferguson, F. G., A. Wikby, P. Maxson, J. Olsson, B. Johansson. 1995. Immune parameters in a longitudinal study of a very old population of Swedish people: a comparison between survivors and nonsurvivors. J. Gerontol. A Biol. Sci. Med. Sci. 50: B378-B382.

Olsson, J., A. Wikby, B. Johansson, S. Lofgren, B. O. Nilsson, F. G. Ferguson. 2000. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech. Ageing Dev. 121: 187-201.

Wikby, A., B. Johansson, J. Olsson, S. Lofgren, B. O. Nilsson, F. Ferguson. 2002. Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp. Gerontol. 37: 445-453.

Wikby, A., F. Ferguson, R. Forsey, J. Thompson, J. Strindhall, S. Lofgren, B. O. Nilsson, J. Ernerudh, G. Pawelec, B. Johansson. 2005. An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J. Gerontol. A Biol. Sci. Med. Sci. 60: 556-565.

Hadrup, S. R., J. Strindhall, T. Kollgaard, T. Seremet, B. Johansson, G. Pawelec, P. thor Straten, A. Wikby. 2006. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J. Immunol. 176: 2645-2653.

Thông tin
Thông tin xuất bản

Journal of Immunology

Tập 179 Số 6

4283-4291

Thông tin tác giả