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Longitudinal studies are defining progressive alterations to the immune system associated with …


Biology Articles » Health and Medicine » Age and immunity » Mechanism

Mechanism
- Age and immunity

The elderly possess more or less the same numbers of peripheral T cells as the young, but as we have seen above, of very different subset and clonal composition. In addition, age-associated alterations on a per-cell basis contribute to immunosenescence, as illustrated by altered signal transduction pathways and processes in cells from old donors. Tamas Fulop (University of Sherbrooke, Canada) gave a general overview on the mechanisms of signal transduction through the T cell receptor, remarking on the key role played by lipid rafts in the formation of the initial complex of signal transduction for T-cell activation. Age-related changes in the cell membrane and specifically impacting on lipid rafts, (cholesterol content, fluidity and signalling molecule composition) may help to explain the severe impairment of CD4+ T-cell signalling observed in ageing, taking also into account that CD4+ T-cell activation completely relies on of lipid raft polarization. Furthermore, a different signalling of the CD28 co-receptor has been shown for the first time among CD4+ and CD8+ T cells from elderly subjects, independent of the measurable CD28 receptor number [19]. This suggests that the physico-chemical properties of the membrane influences more the signalling of a receptor thanthe receptor number per se." [18-20]. In stark contrast, and clearly something that must always be considered when thinking about the emerging differences between CD4 and CD8 cells, activation of the latter is independent of lipid raft polarization. Along the same lines, Anis Larbi (University of Tubigen) compared membrane fluidity and cholesterol content, two key parameters in lipid raft function and consequently TCR signalling, in T cell clones (TCC) derived from CD34+ progenitor cells, young adult donors or centenarians. Cholesterol content decreased while membrane fluidity increased during "in vitro" ageing, but stimulation via the TCR and CD28 led to different phosphorylation patterns depending more on the age of the donor than the in vitro age of the clones. These results possibly suggest that TCC may represent intrinsically divergent properties of the donor cells rather than culture-induced changes [18]. However, they also show that intervention using lipids, either injected or ingested, may result in some degree of immune modulation of potential benefit to the elderly. Further studies on signal transduction, as related to telomerase expression in CD8+ T cells, were presented by Fiona Plunkett (University College, London). Investigating telomere length, telomerase expression, proliferative capacity, and co-stimulatory receptor expression in the various CD8+ CD28/CD27 subpopulations, she showed that CD8+CD28-CD27- T cells have short telomeres and a decreased capacity to up-regulate telomerase in the absence of exogenous cytokines such as IL-2 and IL-15. Using chimeric receptors, it was also shown that up-regulation of telomerase expression in CD8+ T cells can be achieved through other co-stimulatory molecules, such as CD27, CD137 and ICOS, and not only via CD28. This suggests that CD8+CD28-CD27- T cells could still function if given appropriate alternative costimulation and a conducive cytokine milieu for their full activation [21].

Not only does T-helper and cytototoxic cell activation at the single cell level change with ageing, but the frequency and behaviour of regulatory T cells is attracting increased attention once more, also in the context of ageing. The maintenance of immunity has to be balanced with appropriate controls to prevent non-specific inflammation and immunopathology, which it is thought are major problems in ageing. Arne Akbar (University College, London), studying the susceptibility to apoptosis, telomere length, turnover and clonal composition of the regulatory population, reported that CD4+CD25+ T-regulatory cells (T-regs) are generated continuously, most likely by differentiation of CD4+ T-cells in the presence of regulatory cues [23]. These concepts on the mechanisms and dynamic contributing to peripheral tolerance by CD4+CD25+ T-regs, have important implications for the design of therapeutic strategies involving generation and use of CD4CD25+ T-regs in autoimmune and inflammatory diseases. Clearly, their manipulation in ageing will also be of great potential benefit.

Given the difficulty of finding (or defining) naïve cells in the elderly, and given the well-know phenomenon of thymic involution, one focus of attention for researchers interested in immunosenescence must be the thymus itself. As discussed by Richard Aspinall (Imperial College, London) interventionist therapies, based around IL-7, aimed at rejuvenating the thymus to the size and cellularity seen during early life and restoring thymic output, may be an attractive avenue to explore. In particular, treatment with a CCR9/IL-7 fusion protein, which retains its IL-7 activity, seems particularly intriguing because it displays an increased ability to target only the thymus, thus avoiding any side effects of high-dose IL 7 (which may be lymphomagenic). In fact, mice receiving this fusion protein responded better to influenza infection (in terms of CD8 activation, viral load in the lung and change in weight) than IL-7 or untreated animals [22].

Even given the possibility of enhancing naïve T cell generation and improving signal transduction for activation, genomic instability and repair mechanisms of vigorously proliferating cells remains a major concern. Alexander Burkle (University of Constance), reviewed the role of poly(ADP-ribosyl)ation and poly(ADP-ribose) polymerase-1 (PARP-1) in retarding the accumulation of DNA damage and in slowing down the rate of ageing [24]. Molecular genetic approaches to modulate poly(ADP-rybosyl)ation and an innovative method to assess poly(ADP-ribosyl)ation capacity by flow cytometry will facilitate study of and intervention in this critical gatekeeping system. Repair mechanisms in T cells were also addressed by Erminia Mariani and Simona Neri (University of Bologna), who investigated the mismatch repair system (MMR) in T CC derived from hematopoietic stem cells and peripheral T cells from young, old and centenarian donors. By analysing mutations in particular non-coding regions (microsatellites), they observed that in vitro replication increased genomic instability and altered MMR gene expression especially markedly in CD34+ cell-derived clones. This can be seen also in TCC in relation to donor age, suggesting a reduced efficiency of the MMR system during in vitro ageing [25]. Improving DNA repair mechanisms would obviously be a general benefit, not only in ageing but also in cancer and other diseases.

The challenge to find key modulators of immunosenescence and ageing was addressed by Dawn Mazzatti (Unilever R&D Colworth, UK) combining genomic and proteomic investigations on T-lymphocytes isolated from young and old donors, as well as TCC grown to senescence in vitro. The proteins which were demonstrated to be differentially expressed in immunosenescence in TCC following SELDI analysis and further identified by MALDI/ESI-MS/MS were associated with SELDI peaks at 13–14kDa (identified as Histone H2B.q, H2A.5, H2A.q, H2B, and H2B.1) and 8.3–8.5kDa (Tetraubiquitin, chain B and Ubiquitin mutant). Genes found to be differentially expressed in human ex vivo samples during ageing belonged to variety of functional processes which were analysed by Ingenuity Pathway analysis software. These include metabolism, cytoskeleton remodelling, histone organisation, cell-cell communication, signalling and protein degradation. All these gene/proteins might constitute possible targets to ameliorate immunosenescence in the near future. In the meantime, a more direct approach with different antioxidants/ROS scavengers aimed at alleviating the dangerous effects of reactive oxygen species (ROS) on TCC was applied by Yvonne Barnett (Nottingham Trent University, Nottingham). She found that carnosine and N-tert-butyl-α-phenylnitrone (PBN) extended the lifespan of TCC, at the same time as reducing DNA damage. Paradoxically, and contrary to expectations, a superoxide dismutase mimetic (EUK-134) and reduced oxygen tension (6%) culture conditions shortened the lifespan and proliferative capacity of TCCs, despite protecting against DNA damage [26]. These results suggests that better protection against free radicals might be useful to achieve functional longevity extension of human TCCs, but also that functional mechanisms requiring free radical production suggest complexity of applying anti-oxidant approaches in living cells.


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