Preventing or Reversing Immunosenescence

Can Exercise Be an Immunotherapy?

Adriana L de Araújo; Léia CR Silva; Juliana Ruiz Fernandes; Gil Benard

Disclosures

Immunotherapy. 2013;5(8):879-893. 

In This Article

Naive T Cells & Homeostatic Proliferation

One of the major causes of immunosenescence is the severe reduction of the naive T-cell compartment.[26,27] One of the mechanisms is the reduced capacity to generate lymphoid progenitors by functionally impaired hematopoietic stem cells due to a deficiency in the capacity to repair DNA damage.[28] Furthermore, thymic involution is another essential factor contributing to this decline. The thymus is completely developed at birth, but an involution process begins at puberty, in which functional tissue is replaced by fibrofatty tissue. This process persists throughout adulthood, with the thymus being completely involuted by 60 years of age.[29,30] The T-lymphocyte pool decreases dramatically (~80%) with thymic involution, thus affecting the capacity of the adaptive immune system to respond to new antigens. This decrease is observed in lymphoid organs and peripheral blood[31] and is more pronounced in the CD8+ than CD4+ subpopulation,[32–34] suggesting that the latter is more likely to respond to yet-unknown mechanisms of survival.[2]

Therefore, homeostasis of the T-lymphocyte subpopulation is dependent on a mechanism of self-regulation that consists of the homeostatic proliferation of peripheral naive T cells: the organism 'senses the space' left by the contracted T-cell compartment and attempts to restore homeostasis through the proliferation of peripheral naive T cells.[35] In this model, the pool of naive CD4+ T cells is maintained by homeostatic peripheral CD4+ T cell expansion, as demonstrated by a progressive reduction in the T-cell receptor (TCR) excisional circle content (TREC; a replicative cycle marker) with aging. Kilpatrick et al. analyzed the TREC content in two subpopulations of naive CD4+ T cells expressing/not expressing CD31 (which defines newly emigrated thymus CD4+ T cells[36]) in young and old individuals.[37] The authors showed a decrease in CD4+CD31+ naive T cells that was associated with a loss of thymic function and a reduction in the TREC content in the subpopulation of naive CD31 cells in elderly individuals.

In humans, an increased proliferation of CD4+ T lymphocytes has been reported in individuals above 65 years of age and thymectomized children,[38,39] and it is believed that the partial lymphopenia due to the loss of thymus function is responsible for the proliferative increase.[33] In newborns, peripheral T-cell proliferation appears to be responsible for 50% of the daily T-cell production, and this percentage is further elevated in adults.[40] IL-7 and IL-4 are essential for the survival of naive CD4+ T cells[41] and, although the exact mechanisms are not well understood, some in vitro studies in humans have concluded that IL-7 and other cytokines can stimulate T-cell replication without the loss of the naive phenotype.[42,43] In addition, IL-7 can at least partially reverse the reduction in thymopoeisis and thymic output, abbreviating the subsequent immune dysfunction. In this respect, pulmonary administration of IL-7, but not intravenous administration, resulted in a rapid distribution of the cytokine to the tissues of aged animals, promoting a significant increase of the intrathymic development of T cells.[44]

As a consequence of homeostatic proliferation, the naive cells produced by the thymus have a long life cycle, remaining viable in a quiescent state in the peripheral blood.[45] However, it has been argued that the increased survival of naive T cells predisposes them to repeated/prolonged exposure to toxic environmental factors that can cause DNA damage (e.g., mutations).[2] Therefore, homeostatic proliferation can accelerate cell senescence, leading to the shortening of telomeres, the main function of which is to protect the chromosomes ends, helping to maintain the integrity of the genome.[46,47] The telomere is synthesized at the end of DNA replication by the enzyme telomerase, a reverse transcriptase composed of a protein component and an RNA molecule, which contains a template sequence complementary to more than a telomeric repetition and is, thus, capable of preventing progressive shortening of the DNA strand. However, maintenance of telomere length does not occur in human somatic cells because the gene that encodes telomerase is inactive in most cells. Thus, after successive cycles of cellular replication, telomere shortening results in inefficient protection of the chromosomes ends, initiating the process of cellular senescence that, upon reaching a critical point, can result in apoptotic cell death.[47,48] Telomere length can be used to assess the replicative history of cell populations,[49,50] and telomere shortening usually reflects the activity of the 'mitotic watch' by limiting the replicative capacity of somatic cells.[51]

This aging due to increased survival is also associated with a decreased repertoire of naive T cells and an expanded T-cell memory compartment, partially explaining the increased risk of infection and decreased efficacy of vaccination in the elderly.[52]

The role of apoptosis in immunosenescence remains to be clarified. Fas/FasL expression was reported to be increased in naive and memory CD4+ and CD8+ T lymphocytes in elderly individuals (65–95 years old), whereas the antiapoptotic molecule Bcl-2 was decreased compared with lymphocytes from young individuals (20–29 years old). However, a study on centenarians showed that the expression of Fas in memory lymphocytes was increased, although the expression of FasL was reduced.[53] Further studies are necessary to elucidate the role of apoptosis in immunosenescence.

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