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An aged T cell phenotype: A prognostic indicator in liver transplant recipients? Editorial
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Liver Transplantation May 2010
Janet M. Lord
Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham, United Kingdom
email: Janet M. Lord (j.m.lord@bham.ac.uk)
"Shortened leukocyte telomeres are associated with several age-related pathologies, including cardiovascular disease and cancer....the authors show clearly that another possible factor contributing to excess morbidity and mortality in established organ graft recipients is senescence of the immune system as liver graft recipients had shorter T cell telomeres and more cells of a mature phenotype than healthy age-matched controls.....patients with established liver grafts had 1 year added to their T cells' biological clock, whereas patients with hepatocellular carcinoma at transplantation or skin malignancy subsequent to transplantation had 6.2 and 3.7 additional years"
There is now little doubt that aging has a profound effect on both the innate and adaptive arms of the immune system that results in a decline in immunity termed immunosenescence. This is evidenced by increased susceptibility to bacterial and viral infections, reactivation of latent infections (herpes zoster leading to shingles), increased production of autoantibodies, and decreased response to vaccination in older adults. Two key drivers for senescence in the adaptive immune system are thymic involution, which reduces the output of naive T cells, and consequent homeostatic expansion of the peripheral T cell pool.[1] Moreover, with repeated antigen exposure and proliferation of memory T cells throughout life, there is also shortening of telomeres, which limits the proliferative capacity of T cells and eventually results in replicative senescence.[2] With repeated stimulation, T cells also become highly differentiated: they lose costimulatory receptors such as CD28, CD27, cytotoxic T lymphocyte antigen 4, and inducible T cell costimulator, up-regulate inhibitory receptors such as killer cell lectin-like receptor subfamily G member 1, and acquire expression of immune effector molecules, including killer cell immunoglobulin-like receptors, chemokines, and chemokine receptors.[3] Each of these factors contributes to the age-related loss of T cell responsiveness and can be considered a biomarker for the biological age of an individual's immune system.
Importantly, longitudinal studies have revealed that T cell immunosenescence is associated with increased morbidity and mortality, and specific age-related changes in the T cell phenotype have been proposed to represent an immune risk phenotype.[4] Shortened leukocyte telomeres are associated with several age-related pathologies, including cardiovascular disease and cancer, and the number of CD4+CD28- T cells is increased in patients with autoimmune inflammatory diseases such as rheumatoid arthritis. In this issue of Liver Transplantation, Gelson et al.[5] report on their investigation of whether the chronic immune stress of organ transplantation accelerates aging of the immune system. It has already been well documented in the literature that transplant recipients have an increased incidence of cancer, cardiovascular disease, and infections, but this has been largely ascribed to the effects of the long-term use of immunosuppressants. However, the authors show clearly that another possible factor contributing to excess morbidity and mortality in established organ graft recipients is senescence of the immune system as liver graft recipients had shorter T cell telomeres and more cells of a mature phenotype than healthy age-matched controls.
Interestingly, multiple linear regression analyses of case and control data have allowed Gelson et al.[5] to estimate the impact of organ grafts and comorbidities on T cell telomere length, and this has allowed them to gauge the effect in terms of relative T cell aging. Thus, those patients with established liver grafts had 1 year added to their T cells' biological clock, whereas patients with hepatocellular carcinoma at transplantation or skin malignancy subsequent to transplantation had 6.2 and 3.7 additional years, respectively. Crucially, the use of immunosuppressive drugs was not independently associated with shortened telomeres or an increase in cells with a mature phenotype. However, it is possible that these drugs may have contributed to the observation that relative telomere shortening was more marked in the naive T cell pool versus the mature T cell pool. If their effect is primarily on the mature T cells responding to graft antigens via ligation of the T cell receptor with little or no inhibition of the homeostatic expansion of naive T cells, this would lead to a relative sparing of telomeres in the mature T cells.
The important question arising from these data is whether the T cell immunosenescence seen in the established graft patients, equivalent to the addition of only 1 extra year to the T cell age, is enough to affect morbidity and mortality. Longitudinal studies will be required to determine if the T cells in graft recipients continue to age at an accelerated rate, as suggested by the data of Gelson et al.,[5] and if this is associated with an increased incidence of malignancy and infections. In addition, as age was associated independently with shorter telomeres, then one could predict that older graft recipients would have a higher incidence of such postgraft morbidities. Previous studies have indeed reported that age is a pretransplant risk factor in the development of postgraft pathologies, including metabolic syndrome and its components.[6] If accelerated T cell immunosenescence does indeed reflect chronic activation of the adaptive immune system, then shortened telomeres or increased markers of T cell maturation may represent good indicators of patients likely to develop more postgraft complications. As graft recipients are now surviving much longer, we can anticipate that such prognostic indicators will be useful in the long-term management of these patients.
Although Gelson et al.'s[5] data did not find an association between T cell immunosenescence and cardiovascular disease in graft recipients, it would be interesting to analyze other aspects of immunosenescence, such as circulating levels of proinflammatory cytokines or monocyte function, that may be more likely to influence this pathology. The same may hold true for causal factors in the increased risk of infections, such as reduced neutrophil cytotoxicity and natural killer cell cytotoxicity, both of which are associated with aging.[7]
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