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      Cytomegalovirus Infection and Memory T Cell Inflation

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          Abstract

          Cytomegalovirus (CMV) infection in healthy individuals is usually asymptomatic and results in latent infection. CMV reactivation occasionally occurs in healthy individuals according to their immune status over time. T cell responses to CMV are restricted to a limited number of immunodominant epitopes, as compared to responses to other chronic or persistent viruses. This response results in progressive, prolonged expansion of CMV-specific CD8 + T cells, termed 'memory inflation'. The expanded CMV-specific CD8 + T cell population is extraordinarily large and is more prominent in the elderly. CMV-specific CD8 + T cells possess rather similar phenotypic and functional features to those of replicative senescent T cells. In this review, we discuss the general features of CMV-specific inflationary memory T cells and the factors involved in memory inflation.

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          Human T Cell Aging and the Impact of Persistent Viral Infections

          T. Fülöp, A. Larbi, G. Pawelec (2013)
          Aging is associated with a dysregulation of the immune response, loosely termed “immunosenescence.” Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age-associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual. In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age-associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV), which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity. Here, we will review present knowledge of T cell changes with aging and their relation to chronic viral and possibly other persistent infections.
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            T cells and viral persistence: lessons from diverse infections.

            Paul Klenerman, Mary Ann Hill (2005)
            Persistent virus infections create specific problems for their hosts. Although the dynamics of immune responses after acute infection are well studied and very consistent, especially in mouse models, the patterns of responses noted during persistent infection are more complex and differ depending on the infection. In particular, CD8(+) T cell responses differ widely in quantity and quality. In this review we examine these diverse responses and ask how they may arise; in particular, we discuss the function of antigen re-encounter and the CD4(+) T cell responses to and the escape strategies of specific viruses. We focus on studies of four main human pathogens, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus and hepatitis C virus, and their animal models.
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              Cytomegalovirus and human immunosenescence.

              Anis Larbi, Graham Pawelec, Evelyna Derhovanessian … (2008)
              'Immunosenescence' is an imprecise term used to describe deleterious age-associated changes to immune parameters observed in all mammals studied so far. Primarily anecdotal evidence implies that failing immunity is responsible for the increased incidence and severity of infectious disease in old people. However, there is a serious dearth of accurate hard data concerning the actual cause of death in the elderly and the contribution thereto of the multitude of age-associated alterations measured in the immune system. Cross-sectional studies comparing those currently young with those currently old reveal a large number of differences in the distribution of immune cell types in the blood, and to some extent the functional integrity of those cells. Many of these parameters differ markedly between individuals infected with CMV and uninfected people, regardless of infection with other persistent herpesviruses. The adaptive arm of immunity appears to be more seriously affected than the innate arm, particularly the T lymphocytes. However, cross-sectional studies suffer the disadvantage that like is not being compared with like, because the conditions applied during the entire life course of the currently elderly were different from those applied now to the young. These differences in environment, nutrition, pathology and possibly genetics, rather than merely age, may be expected to influence the parameters studied. Moreover, pathogen exposure of the currently elderly was also different from contemporary exposure, probably including CMV. Some of the problems associated with cross-sectional studies can be overcome by performing longitudinal studies, as pointed out in an earlier analysis of the Baltimore Longitudinal Ageing study looking at lymphocyte numbers. However, longitudinal studies are challenging in humans. Nonetheless, the pioneering Swedish OCTO/NONA studies of the very elderly which for the first time included a range of immune parameters, have identified a set of immune parameters predicting mortality at 2, 4 and 6 year follow-up; CMV infection makes a material contribution to this so-called 'immune risk profile (IRP)'. Whether the IRP is informative in younger individuals and the mechanism of the CMV effect is discussed in this review.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Immune Netw
                Journal ID (iso-abbrev): Immune Netw
                Journal ID (publisher-id): IN
                Title: Immune Network
                Publisher: The Korean Association of Immunologists
                ISSN (Print): 1598-2629
                ISSN (Electronic): 2092-6685
                Publication date (Print): August 2015
                Publication date (Electronic): 26 August 2015
                Volume: 15
                Issue: 4
                Pages: 186-190
                Affiliations
                Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea.
                Author notes
                Corresponding Author. Eui-Cheol Shin, Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, Korea. Tel: 82-42-350-4236; Fax: 82-42-350-4240; ecshin@ 123456kaist.ac.kr
                Article
                DOI: 10.4110/in.2015.15.4.186
                PMC ID: 4553256
                SO-VID: 50b7451c-2486-402d-979a-1e83ede15eec
                Copyright © Copyright © 2015 The Korean Association of Immunologists
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 02 July 2015
                Date revision received : 08 August 2015
                Date accepted : 10 August 2015
                Funding
                Funded by: Ministry of Health and Welfare
                Award ID: HI13C1263
                Funded by: National Research Foundation of Korea
                Award ID: NRF-2012-M3C1A1-048860
                Award ID: NRF-2014R1A2A1A10053662
                Funded by: Ministry of Science, ICT and Future Planning
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Immunology
                Keywords: cytomegalovirus,t cells,senescent t cells,memory inflation,immunosenescence
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: cytomegalovirus, t cells, senescent t cells, memory inflation, immunosenescence

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