such as "Introduction", "Conclusion"..etc
This conference was the final meeting of the EU project "T-Cells in Aging", T-CIA . T-CIA brought 8 European centers together for 3 years to study T cell immunosenescence in clonal models in vitro and ex vivo in the elderly. The former focused on long-term cultures of T cell clones (TCC), the latter on longitudinal studies of the very elderly. This work formed the core of the data presented at the meeting in Freudenstadt-Lauterbad, 13–16 December, 2005. The T-CIA project, coordinated by Graham Pawelec (Tübingen University) evolved from the earlier EU-supported networking projects EUCAMBIS and ImAginE, and has investigated human T-cell immunosenescence in vivo end in vitro with the aim of increasing the understanding of immune ageing and laying the preclinical groundwork for rational intervention.
Senescence of clonotypic immunity is thought to be principally a result of the declining effectiveness of T cells. Lifelong exposure to chronic antigenic load is the major driving force of immunosenescence, impacting on human lifespan by reducing the number of naïve antigen-non-experienced T cells, and, simultaneously, filling the immunological space with expanded clones of memory and effector, antigen-experienced T cells . Gradually, the T-cell population shifts to a lower ratio of naïve to memory cells, the thymus generates fewer naïve T cells with age and those T cells remaining, especially the CD8+ subset, also show increased oligoclonality with age. Thus, the repertoire of cells available to respond to antigenic challenge from previously unencountered pathogens is shrinking. In addition, older individuals commonly possess memory cells carrying a single T cell receptor, i.e. they represent clonal expansions. Thus, the memory cells from old individuals might recognize a limited set of antigens despite being plentiful in number. Many of the clonal expansions crowding an elderly person's immune system result from previous infections by persistent viruses, resulting in the presence of many CD8+ cells specific for a limited number of epitopes of herpes viruses: in some individuals more than 10% of peripheral CD8 cells react against a single CMV epitope . Here, then, there is potential for intervention, both prophylactic (vaccination), therapeutic (anti-virals) and immunologic (deletion of dysfunctional cells). A novel approach to the latter was suggested by Katsuiku Hirokawa (Tokyo Medical & Dental University) who proposed banking peripheral T cells from younger individuals, depleting their dysfunctional cells in later life, and replenishing from the frozen bank of young T cells. This type of "mini-transplant" is standard procedure in cancer therapy. Memory T cells usually carry the CD28 surface protein, which helps stimulate the cells to divide when antigen is present. But old memory cells tend to lose CD28 and, as a result, multiply less robustly when exposed to antigen than do younger cells . Here, therefore, is another opportunity for intervention: cause re-upregulation of CD28, either by gene therapy or application of cytokines such as interleukin (IL)-12 or antibodies neutralising tumor necrosis factor (TNF)-α. As a consequence of the above events, if unchecked, T and B immunosenescence and, likely, mortality and morbidity, will occur earlier in people that have been exposed to an antigenic overload (due to chronic infections). The opposite situation may apply to people exposed to a lower antigenic load and/or with an appropriate immunogenetic background. This implies that the ability of our immune system is progressively worn down by the need to maintain immunosurveillance against persistent pathogens or other sources of antigen, such as cancer .
For the reasons discussed above, a good part of the meeting, like the elderly immune system, was obsessed with CMV. Paul Moss (University of Birmingham) showed that cytomegalovirus infection at any stage in life adds more age to the ageing process with respect to the naïve compartment. Indeed, the immune response to CMV can account for around 25% of all the clonal CD8+ T cell populations that are known to accumulate with ageing. Concomitantly, the absolute T cell count is increased by 20% in elderly donors who are CMV-positive compared with CMV sero-negative. This correlates with the absolute count of CD8+ T cells doubling in the CMV-seropositive cohort and with the CD8+CD28- subset dramatically increased 5-fold. Because CMV infection results in such strong T cell responses, methods to control infection and to prevent reactivation through vaccination might be beneficial . According to the old adage "know your enemy" maximising our information on CMV-immune system interactions might also facilitate control of the beast. Stefan Stevanovic (University of Tübingen) investigated CMV-specific T cell responses in a large number of healthy donors of different human leukocyte antigen (HLA) types and found that as previously reported, almost all HLA-A*01-, A*02-, and B*07- positive individuals had TCR specific for a limkited range of immunodominant epitopes. However, people with other HLA-allotypes did not mediate such immunodominant responses, suggesting that control by vaccination with a limited number of epitopes may be more complicated .
In the elderly, Rafael Solana (University of Cordoba) observed higher percentages of CMV-specific CD8 effector memory cells, and showed that it was these cells which predominantly expressed enhanced levels of HLA class-I-specific and non-specific NK receptors . These results suggest that interactions usually occurring within the innate immune system will need to be taken into count when considering CMV control strategies. Paolo Sansoni (University of Parma) confirmed that age-associated CD8+ T clonal expansion could be related to increased frequency of CMV infection. In particular, CD28- T cells accumulate, with age, only in seropositive subjects both within CD4+ and CD8+ cells while reduction of naïve T cells is more profound among CMV-seropositive subjects within CD8+ T cells. He also found that IFN-γ -producing cells specific for at least one immunodominant CMV protein within CD8+ or CD4+ subsets increase with age . These results indicate that while attention has focussed on the larger clonal expansions seen in CD8 cells, effects on CD4 cells are also likely to be critical in shaping the elderly immune response.
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