Effect of cellular aging on memory T-cell homeostasis

Abstract

The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this ‘homeostatic’ regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, ‘global’ competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional ‘cognate’ competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the ‘gold-standard’. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for ‘cognate’ competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the ‘gold-standard’ level of TCR diversity in the memory T-cell pool.

The dynamics and longevity of circulating CD4+memory T cells depend on cell age and not the chronological age of the host

“…This dynamic will lead to the accumulation of older memory CD4 T cells. In contrast, a recent study argued that an increase in cell mortality with cell age may act to preserve the TCR diversity of memory populations as an individual ages, and hence be beneficial [38]. In the latter study, cell aging was directly associated with cell divisions, whereas here we defined age to be a heritable clock that measures the time since a cell’s ancestor entered the memory pool.…”

Memories that last: Dynamics of memory T cells throughout the body

“…Based on in silico simulations, in which memory T cells compete for survival or proliferation factors, we have recently shown that the diversity of the memory T‐cell repertoire tends to reach higher levels if memory T cells are relatively short‐lived. A relatively rapid turnover of memory T cells creates more flexibility to store new memories, and hence makes the immune system more agile 113 …”

“…A relatively rapid turnover of memory T cells creates more flexibility to store new memories, and hence makes the immune system more agile. 113 The observed differences between clean laboratory mice and mice exposed to wild microbiota raise the question how memory T-cell dynamics may differ between humans living in environments with different levels of exposure to pathogens. Weisman et al 114 recently demonstrated the drastic effects that helminth infections can have on the T-cell pool.…”

Strategies for modeling aging and age-related diseases

“…Aging in animals and especially in humans is the natural result of entropy in cells as part of tissues and organs of the human body. It is a slow, inexorable process that leads to a continuous increase in molecular errors in DNA and proteins, increasingly disrupting the homeostasis of cells, tissues, and organs 3 , 4 . Accordingly, a set of tools has been established to analyze aging on a cellular level.…”