One of the signature immunological changes that accompanies aging is the accumulation of CD8 T cells lacking the CD28 co-stimulatory molecule (dubbed CD8+ CD28- T cells). Several studies have found that in elderly cohorts, increased numbers of CD8+CD28- T cells are associated with a significantly elevated risk of mortality. These studies have also reported that elderly people with CMV infection have higher numbers of CD8+CD28- T cells than comparable CMV seronegative individuals. These findings have parallels in HIV because CD8+CD28- T cells accumulate far more rapidly in people with HIV than in uninfected individuals, and a recent study reported that increased numbers of these cells are associated with more rapid progression to AIDS and death.
Current evidence suggests that CD8+ CD28- T cells are functionally impaired due to chronic stimulation and represent a “senescent” population. The evidence includes shortened telomeres (which shorten in cells as a result of proliferation), resistance to cell death (apoptosis), reduced response to normal immune signaling and production of high levels of interferon gamma. There are also studies indicating that this functional profile causes CD8+ CD28- T cells to contribute to detrimental inflammatory processes in the elderly (sometimes referred to as “inflammaging”).
Suspicions that CD8+ CD28- T cells are bad actors in a variety of disease processes, including HIV, has led some researchers to propose that they should simply be removed, although exactly how this might be accomplished has not been detailed (at least to the best of my knowledge). The goal would be to allow more functional T cells to expand and take up the “immunological space” being occupied by the senescent CD8+ CD28- T cells.
This therapeutic idea prompted Birgit Weinberger and colleagues to take a preliminary look at whether antigens being targeted by CD8+ CD28- T cells are also targeted by other CD8+ CD28+ T cells, based on the concern that removal of the CD28- population might inadvertently eliminate important immune responses. The study sampled T cells from six donors with a median age of 70. Responses to a CMV epitope from the pp65 protein were measured, and the researchers found that they were present among both CD8+ CD28- and CD8+ CD28+ T cells.
Although they stress the preliminary nature of the work, the authors interpret their findings as suggesting: “Elimination of CD28- T cells in order to create more immunological space and consequently to allow the regeneration and rejuvenation of the aged T cell system would…not lead to the loss of important specificities. Viral control would be intact due to the recruitment and propagation of the relevant clones from naïve or early memory T cell populations.” Due to the increased attention being paid to immunosenescence, both in HIV-infected and uninfected individuals, it seems likely that the potential for removing CD28- cells will be explored in animal models before too long.
Article in Press, Uncorrected Proof
Birgit Weinberger a, Kathrin Welzl a, Dietmar Herndler-Brandstetter a, Walther Parson b and Beatrix Grubeck-Loebenstein a.
a Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, 6020 Innsbruck, Austria
b Institute of Legal Medicine, Innsbruck Medical University, Müllerstr. 44, 6020 Innsbruck, Austria
Highly differentiated CD28 effector T cells which accumulate in a variety of diseases and also with increasing age contribute to inflammatory processes, limit immunological space and diversity, and are associated with immunological dysfunction and reduced responses to vaccination. Elimination of CD28 T cells has been suggested as a measure for immunological rejuvenation but may lead to the loss of important T cell specificities. Using T cells specific for the immunodominant CMV-derived epitope NLVPMVATV as a model, we show that the same clonotypes are present in CD8+CD28+ naïve/early memory and CD8+CD28 effector T cells. Therefore, CD28 cells do not seem to contain clones which are not present in the residual population. The elimination of effector T cells would not lead to the loss of important specificities, as relevant clonotypes could be recruited and propagated from naïve or early memory T cell subsets in the case of exposure to pathogen.