Immunosenescence: Analysis and Genetic Modulation of Replicative Senescence in T Cells

Summary: T-cell senescence might be an important part of aging.

Interestingness: 4

Paper by Rita B Effros and Hector F Valenzuela in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((These people want to try out upregulating telomerase in old T-cells)))

A major part of the function of T- and B-lymphocytes is based on replication. When differentiating from hematopoietic stem cells, the molecules or particles which the future mature lymphocytes are sensitive to (aka antigens) are encoded by a few sequences of DNA which are combined in random fashion. This makes the system potentially sensitive to hundreds of millions of different antigens. When an antigen is bound by a lymphocyte, the lymphocyte starts replicating, making identical clones (ie their receptor which sensed the antigen is not modified). When the antigen is no longer found in the environment, most of the lymphocytes disappear, but a few memory lymphocytes with the particular receptor remain so that the system can be revved up faster the next time that specific antigen is in the system.

Senescent T-cells can be generated in vitro by repeatedly exposing them to interleukin-2 (IL-2), a T-cell specific growth factor. After about 25-40 replications, they become senescent (ie they stop replicating). Fibroblasts (connective tissue cells) also become senescent after about 21 replications.

The receptor CD28 is not expressed in 95% of CD8+ senescent T-cells, and in all CD4+ senescent T-cells. Without CD28 costimulation, antigen binding doesn't lead to cell replication. CD28 signal transduction upregulates IL-2. It is also hypothesised to upregulate telomerase activity. Telomerase is very active in lymphocytes under certain conditions: in developing T-cells in the thymus and in lymphoid organs, when stimulated with mitogens (particles that upregulate replication), or by combination of antibodies to CD3 and CD28. When CD28 binding is inhibited, telomerase remains inactive even if there is strong stimulation of its T-cell antigen receptor (TCR). Even though telomerase is sometimes active in T-cells, senescent T-cells have short telomeres typical of other senescent cells. When split into CD28+ and CD28- T-cells, CD28- cells have shorter telomeres and lower replicative capacity when stimulated.

In vivo, CD28- T-cells are 1% fraction of neonates' total T-cells, 30% of (average) 78 year olds, 40% of people over 100, and 50% of HIV patients. Telomere lengths also shorten in peripheral blood lymphocytes as age increases. This loss of CD28 and shortening of telomeres is more pronounced in CD8+ cells, which specialise in anti-viral and anti-tumor activity, than in CD4+ cells (((doesn't this contradict the earlier numbers of 95% in CD8 and all in CD4?))). This could be due to infections by viruses that do not disappear (eg Epstein-Barr, varicella) or by repeated infections (eg influenza).

As people age, memory T-cells become a larger fraction of all T-cells. Senescence is also more common among memory cells. Non-senescent T-cells in old people respond to activation as strongly as those in young people.

During normal immune system activity, once the antigen dissapears from the system, most T-cells die by apoptosis. Senescent cells respond to apoptotic signals much less strongly, especially among CD8+ cells. These leftovers memory T-cells could be crowding out the production of new more useful T-cells. In calorie restricted mice, apoptotic response is maintained at youthful levels.



Abstract follows:

Immunosenescence, which constitutes one of the most dramatic physiologic changes associated with aging, may account for the increased susceptibility to infections and the high incidence of cancer in the elderly. A novel facet of T-cell biology has been recently identified that may exert a considerable impact on immune control over infections and cancer during aging. Cell culture studies have shown that after repeated rounds of antigen-driven proliferation, T lymphocytes eventually reach replicative senescence, an irreversible nonproliferative state associated with the loss of expression of a critical T-cell signaling molecule. Identification of this unique, cell-specific marker of senescence has facilitated the documentation and analysis of replicative senescence within the immune system in vivo during aging. This article summarizes the features of T-cell replicative senescence and highlights several genetic strategies that may reverse the process. The ability to manipulate T-cell replicative senescence may ultimately provide a fresh therapeutic approach to extend the years of immunologie "coverage" in the elderly.