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Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people.
Over the past century life expectancy in the developed countries has dramatically increased from an mean age of 50 years to a mean of 80 years. The increase in life expectancy is mainly due to better living conditions and improved medical care. Nowadays people live twice as long as before, but this increase in life expectancy has not come without a price, it is accompanied by an enormous increase in age associated diseases like Alzheimer's, atherosclerosis, diabetes, cancer etc. (1) The complex process of aging effects many functions throughout the body including the immune system, which now has to remain active almost twice as long as it was evolutionary designed. As people get older the immune system undergoes various changes, collectively termed immunosenescence. (1). Immunosenescence describes a state of profound age-associated changes in the immune system (2) and is characterized by the overall decline of antigen-specific immunity. At the cellular level the most important changes are the markedly decreased number of naïve T-lymphocytes as a result of reduced T-cell production due to age-associated thymic involution. Furthermore senescence is characterized by a increased amount of oligoclonally expanded and functional incompetent memory lymphocytes. (2) As a result of immunosenescence elderly people are often more susceptible to disease and show a reduced response to vaccination. In particular the ability to control disease caused by novel pathogens is compromised and it is thought that the response to previous-encountered pathogens is also eroded in the elderly. (3)
Currently there are two hypothesises in which the immune system could be compromised. The first hypothesis states that T-cells from elderly donors are in some way compromised in its function. The the second hypothesis states that the proportions of T-cell subsets may differ between young and old people, but that the function of each cell type is the same regardless of donor age. Evidence supporting both hypothesis have been found but more research needs to be done to determine which hypothesis explains the T cell changes in the elderly. (3)
Figure 1 (3)
Because it is difficult to define a T-cell subset several models have been proposed based on cell surface expression of receptors and molecules. Koch et all. based their research on the models of Sallusto and Romero to investigate the differences between T-cell subsets in young and old people. The model proposed by Sallusto et all. divides CD8 cells on the basis of their expression of the leukocyte common antigen isoform CD45RA and the chemokine receptor CCR7 into naïve (N; CD57RA+ CCR7+), central memory (CM; CD57RA- CCR7+), effector memory (EM; CD45RA- CCR7-) and terminally differentiated effector memory cells (TEMRA; CD57RA+ CCR7-) (4) Romero et all. subdivided the main subsets further by their expression of the co-stimulatory molecules CD27 and CD28. N and CM cells were defined as CD27+ CD28+ whereas in EM and TEMRA more populations could be distinguished. (figure 1) (3)
Because differences between the previous described T-cell populations in young and old people have not been investigated, but could give new information about T-cell (subset) changes in the elderly, Koch et all tried to identify changes in the T-cell subsets between young and old. New insights in how T-cells differentiate and the changes in T-cell populations during aging could tell us wether T-cell changes in the elderly are caused by altered frequencies of different T-cell subsets or by altered properties within the different subsets. The aim of this study was to investigate the frequencies of the different T cell subsets in young and old donors based on the model described above. (3)
In this study they used PBMC of people from several different European countries with a mean age of 40 (53% female) or 87 (66% female). Polychromatic flow cytometry with antibodies to CD27, CD28 CCR7 and CD45RA was performed to investigate the frequencies of the different T-cell subsets in young and old donors. In their studie they not only looked at CD8 cells but also extended the model discussed above to CD4 cells. Furthermore they also included two other putative markers of highly differentiated T cells into their analysis, namely CD57 and KLRG1. KLRG1 is associated with replicatively senescent cells and CD57 is associated with terminally differentiated cells with reduced proliferative capacity.
The results of their research showed that during aging there is a shift in T-cell subsets. They confirmed by analysis using CD57RA and CCR7 antibodies that during aging in PBMC naïve CD8 cell subsets decrease and TEMRA cells subsets increase. When dissected further by their expression of CD27, CD28 CD57 and KLRG1 even greater age-associated differences were found. The differences found were more marked in CD8 than in CD4 cells, but a similar overall pattern prevailed in both.
The use of all these markers together enabled them to construct a differentiation scheme applicable to CD4 as well as CD8 cells, with the model (based on Romero et al.) suggesting the progression of cells from N-->CM-->EM1-->EM2-->pE1-->pE2-->EM4-->EM3-->E to end-stage non-proliferative effector cells.
Koch et all. furthermore conclude in their study that Polychromatic flow cytometry can be a powerful tool in examining changes in the immune parameters in elderly people. By combining analyses using antibodies to CD27, CD28 CCR7, CD45RA, CD57 and KLRG-1, the results found show the robustness of the decrease in naïve an increase of late differentiated CD8 cells with age with a similar tendency in CD4 cells in different populations with dissimilar genetic, nutritional an pathogen-exposure backgrounds. This approach facilitates the analysis of age-associated immune alterations in humans in minor detail. Overall, the results suggest that both differences in subset distribution and differences between subsets are responsible for age-related changes in CD8 cells but that differences within rather than between subsets are more prominent for CD4 cells. (3)
This studie was an important studie and should be published in an excellent journal because in this studie Koch et all. for the first time investigated the differences between T-cell subsets in young and old people, and showed that their findings are likely to be generally applicable and independantly of genetic or environmental background. They for the first time used polychromatic flow cytometry which allowed them to use constellations of markers for a finer definition of subsets at the single cell level. The most important conclusion is that which this tool the age-associated immune alterations can be investigated in minor detail. Furthermore they constructed a new differentiation scheme by which T-cells differentiate from naïve to end-stage non-proliferative effector cells.
The strenghts of this article are that they used a new polychromatic flow cytometry tecnique.
This because the differentiation stages of CD8 T-cells can be ordened using models like the one of sallusto et all. however it is impossible to get an absolute correlation between the differentiation state of the T-cells and expression of the surface molecules. Combinations of markers like Koch et all. did in their research may improve the abillity to dissect out different subtypes. The use of polychromatic flow cytometry for the first time allows constellations of markers to be used together for a finer definition of subsets. Furthermore for their study material they selected a heterogenous cohort of young and old donors over a wide age range and from different European countries, in this way any statistical differences found are likely to be generally applicable and independent of genetic or environmental background. This strengthens their results found that the expected age-associated reduction in naïve cell population is clearly seen in CD8+ cells as well as the Increase in TEMRA cells. Furthermore they expanded their research to the CD4 T-cells were not a lot of information is known about.
What is important to mention is that the models they used are all conceptual models, T-cell lineages are not fixed but in a dynamic state of differentiation.
This research doesn't change the field dramaticly but is important for further research on T-cell changes in immunosenescense. The study performed by Koch et al is primarily a fundamental research, there are no ethic considerations and no prospects for a possible theraphy yet. This research is however very important, when it is know how T-cells differentiate this knowlage may be used for therapeutic opportunities. It may for example be possible to influence the T-cell differentiation in a way that T-cells will not differentiate to terminally differentiated cells. Overall the research peroformed by Koch et all was a well performed research and has opened new doors for further research.
1 Kovaiou RD, Herndler-Brandstetter D, Grubeck-Loebenstein B. Age-related changes in immunity: implications for vaccination in the elderly. Expert Rev Mol Med. 2007;9:1-17. doi: 10.1017/S1462399407000221
2 Weng NP. Aging of the immune system: how much can the adaptive immune system adapt? Immunity. 2006;24:495-499. doi: 10.1016/j.immuni.2006.05.001.
3 Koch S, Larbi A, Derhovanessian E, -zcelik D, Naumova E, and Pawelec G. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing. 2008; 5: 6. doi: 10.1186/1742-4933-5-6
4 Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708-712. doi: 10.1038/44385
5 Romero P, Zippelius A, Kurth I, Pittet MJ, Touvrey C, Iancu EM, Corthesy P, Devevre E, Speiser DE, Rufer N. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J Immunol. 2007;178:4112-4119