As shown in , aging results in a shift toward the myeloid lineage with expansion of the myeloid progenitor cell population at the expense of lymphoid progenitors. In addition from late childhood in humans the thymus atrophies leading to a 3% decline in thymic output of naive T lymphocytes per year. As the peripheral lymphocyte pool remains constant the homeostatic balance is maintained by expansion of the peripheral pool, resulting in an increase in the ratio of memory to naive T cells with age.
Figure 1. Blood cell generation from the pluripotent stem cell showing predisposition toward the myeloid lineage with aging.
The increase in memory T cells with age is potentially advantageous as the host essentially develops a memory cell repertoire against the pathogens encountered on a regular basis. However, lymphocytes cannot proliferate indefinitely and lymphocyte proliferative senescence is another factor contributing to immunesenescence, leading to re-emergence of infections that the person was previously immune to. An example of the latter includes Varicella zoster
acquired in childhood giving chicken pox and emerging as shingles in old age. The loss of proliferative capacity is a result of the shortening of telomeres. Telomeres located at the tip of chromosomes range from 4 to 12 Kb in humans and protect coding-DNA from degradation and confer stability to the chromosome. Telomere length decreases with each round of cell division (50–100 bp per division). In the absence of compensatory mechanisms, telomeres eventually reach a critical length which leads to growth arrest and diminished lymphocyte proliferation. Telomerase has a role as this enzyme is expressed in lymphocytes and is a reverse transcriptase that synthesizes telomeric repeats and allows these cells to proliferate much more than other cells in the body. A study from Arne Akbar’s group demonstrated substantial telomere erosion and loss of replicative capacity of CD8+
T cells during aging.8
As summarized in , in healthy individuals, the generation of new T cells progressively declines due to thymic atrophy. This decline is compensated for by the homeostatic proliferation of mature T cells in the periphery. Eventually, the continually replicating mature T cells become exhausted due to telomere shortening and take on a senescent phenotype characterized by blunted replicative potential, contracted T-cell repertoire, loss of CD28 co-stimulatory receptor expression, and de novo expression of stimulatory receptors such as killer-like immunoglobulin receptors (KIR).9
Figure 2. The effects of aging on T cell proliferative capacity and phenotype.
It has been reported that persistent CMV infection is a major factor in T cell immunesenescence, driving T cells toward inexorable end-stage differentiation, shortening telomeres which may eventually lead to the loss of functional CMV-specific memory T cells in older subjects and reduced vaccination responses.10
In addition CMV specific T cells dominate the peripheral pool, with levels in excess of 10% seen in some older subjects,8
leading to the immunological space being occupied by large numbers of cells with poor proliferative capacity. The T cell receptor Vβ repertoire of CMV-specific CD4 T cells like the CMV-specific CD8 T cell population is highly restricted in both young and old subjects. Evidence suggests that CMV-specific CD4 T cells may have reduced capacity to induce telomerase and that this may be one reason for their short telomeres. It has also been suggested that CMV-specific CD4 T cell populations are susceptible to replicative senescence upon repeated stimulation since they have short telomeres and have lost their ability to induce telomerase after activation.11
Thus, CMV-specific CD4 T cell expansion limits immune responses due to high frequency, highly differentiated surface phenotype, having significantly shorter telomeres, low telomerase activity and reduced replicative capacity.