Opinion TRENDS in Immunology Vol.25 No.8 August 2004 Is immunosenescence infectious? Graham Pawelec1, Arne Akbar2, Calogero Caruso3, Rita Effros4, Beatrix Grubeck-Loebenstein5 and Anders Wikby6 1University of Tu¨ bingen Medical School, Center for Medical Research, ZMF, Waldho¨ rnlestr 22, D-72072 Tu¨ bingen, Germany 2Department of Immunology and Molecular Pathology, The Windeyer Institute For Medical Sciences, Royal Free and University College Medical School, 46 Cleveland Street, London W1T 4JF, UK 3Universita` di Palermo, Dipartimento di Biopatologia e Metedologie Biomediche, Gruppo di Studio sull’Immunosenescenza, Corso Tukory 211, 90134 Palermo, Italy 4David Geffen School of Medicine at UCLA, Department of Pathology and Laboratory Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA 5Austrian Academy of Sciences, Institute for Biomedical Ageing Research, Immunology Division, Rennweg 10, A-6020 Innsbruck, Austria 6School of Health Sciences, Jo¨ nko¨ ping University, Department of Natural Science and Biomedicine, P.O. Box 2038, Banarpsgatan 39, SE-551 11 Jo¨ nko¨ ping, Sweden Herpes viruses are endemic. Once established, the virus of CMV status [4]. That study reported that CMV is never eliminated but persists throughout life. The seropositivity was associated with an increased number fraction of infected individuals gradually increases with of both CD4þ and CD8þ cells, which were CD282. age, such that the majority of elderly people are cyto- Importantly, the authors pointed out that this phenotype megalovirus (CMV)1, Epstein–Barr virus (EBV)1 and had previously been associated with age; however, they Varicella1. Clinically relevant reactivation of Varicella found that it was primarily associated with CMV status causes painful shingles; CMV reactivation can cause and only secondarily with age, given the increasing fatal pneumonia. Overt reactivation, even in the very frequency of CMV-infection with age. However, both age elderly, occurs only in immunocompromised individ- and CMV status influenced the number of CD8þ cells and uals; however, the necessity for maintaining immunity their expression of CD45RA and CD28. to these viruses is costly. We argue that this cost is not only reflected in the requirement for continuous immu- Role of CMV in determining the ‘immune risk phenotype’ nosurveillance against these viruses but, more impor- Age-associated changes in the immune system have been tantly, results in a re-configuration of T-cell immunity extensively documented over the years, without reference due to the accumulation of dysfunctional virus-specific to CMV status (Box 1). However, two different approaches cells, which fail to be eliminated from the system. Thus, have recently begun to shed more light on the unexpected we hypothesize that it is the chronic antigenic stimu- way in which CMV infection shapes the ageing human lation by CMV (and possibly other persisting antigens) immune system. The first is the development of tetramer that leads to an increasing prevalence of senescent, technology, enabling direct identification of T cells carry- dysfunctional T cells, and therefore contributes to more ing receptors for single peptide epitopes. The second is the general alterations in the immune system, which are associated with earlier mortality. Box 1. Alterations in the T-cell compartment with age Maintenance of protective immunity against cytomegalo- " CD45ROþ cells (reviewed in Ref. [41]) virus (CMV) is clearly essential, which is graphically " CD95þ cells (reviewed in Ref. [41]) illustrated by earlier experiences in bone marrow trans- # CD28 expression (reviewed in Ref. [41]) plantation (reviewed in Ref. [1]). Nonetheless, early " CD152 expression (reviewed in Ref. [41]) reports of viral reactivation suggest that immunity is a " killer cell lectin-like receptor G1 (KLRG-1) expression [15] continuous battle even in normal healthy persons [2].At # apoptosis of CD8 cells (reviewed in Ref. [41]) " apoptosis of CD4 cells (reviewed in Ref. [41]) that time, the composition of the different T-cell subsets # interferon-g (IFN-g) production; meta-analysis [42]a was just being identified, and, concurrently, reports were # ? interleukin-2 (IL 2) production; meta-analysis [42]b appearing that CMV infection could markedly alter # telomere lengths (reviewed in Ref. [41]) components of those subsets [3]. One of the early studies # telomerase induction (reviewed in Ref. [41]) þ " DNA damage (reviewed in Ref. [41]) showed an increased number of CD8 cells in normal # DNA repair (reviewed in Ref. [41]) healthy donors and even identified expansions of # stress resistance and heat-shock protein (HSP) expression þ þ þ CD8 CD57 (HNK-1 ) subsets in CMV seropositive (reviewed in Ref. [41]) individuals. It was over a decade later that differences aData from meta-analysis: of 23 studies, 11 reported decreased IFN-g between young and old donors were assessed in the context production, 8 no change and 4 an increase. bData from meta-analysis: of 28 studies, 14 reported decreased IL 2 production, 3 no change and 11 an increase. Corresponding author: Graham Pawelec ([email protected]). Available online 2 June 2004 www.sciencedirect.com 1471-4906/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2004.05.006 Opinion TRENDS in Immunology Vol.25 No.8 August 2004 407 deployment of longitudinal studies of the naturally ageing population, marked expansions of CD8þCD282 cells are population to begin to identify factors predicting mortality. frequently found in the elderly and that large numbers of In the Swedish longitudinal study, known as the OCTO these cells have receptors of exactly this CMV specificity study [5], age-related changes in several immune par- [13]. These expansions presumably represent an adaptive ameters are being investigated by monitoring a free-living physiological response, emphasizing the importance of population over time. Values for a cluster of parameters, controlling CMV [and other herpes viruses: Epstein–Barr including high CD8, low CD4 and poor proliferative virus (EBV)-specific T cells are also more frequent in the response to concanavalin A (Con A), were found to predict elderly than in the young, although their frequency is ten- higher two-year mortality in a relatively homogeneous fold lower than the CMV-specific cells [14]]. But why are population from this one city, selected only by virtue of they commonly present in much larger numbers than in having survived to the age of 80 [6]. This cluster was the young? One clue came from the discovery that a very designated the ‘immune risk phenotype’ (IRP) [7] (Box 2). high proportion of such CMV-specific cells in these elderly These results were confirmed in a second two-year follow- also expressed high levels of the negative regulatory killer up, which also showed that additional individuals had cell lectin-like receptor G1 (KLRG-1) [15]. This molecule is moved into the IRP category during those two years [8]. thought to be present on end-stage senescent cells, which, Later, it became apparent that CMV seropositivity was although they might retain cytotoxic function, are less able significantly associated with the IRP [9]. The immune to secrete cytokines, such as the antiviral agent interferon-g changes were confirmed in the subsequent Swedish NONA (IFN-g). It is possible that the ability to secrete IFN-g is longitudinal study [10], which pinpointed the CD8þ- more important for maintaining immunosurveillance than CD272CD282CD57þCD45RAþ phenotype as markedly direct cytotoxicity, at least in the case of CMV. Moreover, expanded for individuals in the risk category. Importantly, there was a significant correlation between the degree of this study also indicated that the risk phenotype was expansion of these CMV-specific cells and the assignment independent of the health status of the individual at that of the donor to the IRP category. Follow-up studies on these particular time [11]. Therefore, at least in the already donors are being performed. elderly population, a cluster of immune parameters, Other investigators have shown that expansions of including CMV status, can be identified, which accurately CMV-specific cells in the elderly are indeed clonal, predicts mortality. What causes an individual to reside in occasionally biclonal [16]. This study also used tetramers containing a second CMV epitope, this time restricted by the IRP category or to move into it as they age? Our an HLA-B allele. They made the important discovery hypothesis is that this state is strongly influenced by the that when an elderly donor carried both the HLA-A and ability of the individual to manage the consequences of -B alleles, T-cell expansions to only one of the two epitopes CMV infection. are seen (HLA-B-restricted responses being dominant over The OCTO and NONA samples have now also been HLA-A-restricted). Thus, it is necessary to examine a examined using MHC–peptide tetramers capable of larger number of epitopes on a bigger set of HLA alleles to identifying CD8þ T cells from HLA-A*0201þ donors; get the full picture. Moreover, these studies addressed only these CD8þ T cells carry T-cell receptors for the immuno- CD8þ cells because the production of MHC class II dominant human CMV pp65-derived epitope Nlvpmvatv. tetramers has thus far proven difficult. Using whole Although these studies were limited to only one HLA allele CMV antigen and cytoplasmic cytokine staining, however, and one CMV epitope, interesting preliminary data have þ large numbers of CMV-reactive