An aged T cell phenotype: A prognostic indicator in liver transplant recipients?

Abstract

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. 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. 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. Each of these factors contributes to the agerelated 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. Shortened leukocyte telomeres are associated with several agerelated pathologies, including cardiovascular disease and cancer, and the number of CD4þCD28 T cells is increased in patients with autoimmune inflammatory diseases such as rheumatoid arthritis. In this issue of Liver Transplantation, Gelson et al. 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. 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