This open access paper discusses a secondary issue in the aging of the adaptive immune system. Of primary concern is that the supply of new T cells diminishes over time, due to the atrophy of the thymus where such cells mature, as well as due to issues in the hematopoietic system of the bone marrow where such cells are produced. As noted here, a secondary concern is that the population of unspecialized naive T cells needed to respond effectively to novel threats begins to have issues maintaining itself in readiness. So not only is the supply of new naive T cells reduced to a tiny fraction of youthful levels, but the population present at any given time corrodes into ineffectiveness more rapidly.
A key feature of age-related immune erosion (termed "immune aging") is the loss of naïve T cells. This loss is often attributed to the involution of the thymus during adulthood however naïve T cells can be maintained for decades by homeostatic proliferation within lymph nodes and secondary lymphoid tissues. Naïve cell loss is instead caused by a breakdown in peripheral homeostasis during the aging process. Naïve T cell homeostasis is multi-faceted, requiring both cell survival and the retention of a quiescent state. Recent studies in humans highlight that naïve cells not only decline numerically in lymph nodes, but they also break quiescence, acquiring a distinct, partially differentiated state during aging.
Stem cell quiescence is a reversible state of growth arrest that plays an important role in tissue homeostasis and regeneration. Recent work in the area of stem cell biology has established that quiescence is not a passive process but is actively maintained by transcriptional and post-transcriptional regulation, including chromatin modification and microRNA-mediated gene repression. Notably, there are distinct levels of stem cell quiescence, ranging from 'deep' to 'shallow' that correlated with more rapid responses and altered functional capacity in both mice and man.
Biologically, naïve T cells are relatively similar to quiescent stem cells, particularly in their high pluripotency and proliferative potential. However, unlike stem cells, the extracellular cues for exit from quiescence are unique to naïve T cells. These cells classically retain a quiescence state until they encounter a specific antigen within their local lymph node niche. Upon direct antigen activation, naïve T cells exit quiescence, rapidly proliferate and can differentiate into numerous functional states depending on numerous factors including the local cytokine and cellular milieu.
In turn, the regulation of activation and the maintenance of cellular quiescence in T cells is extremely important for immune homeostasis, as its failure can lead to significantly perturbed immunity, such as autoimmune disease, cancer, or increased infection. In aging, proliferation capacity of naïve T cells appears intact however pluripotency is diminished; naïve T cells from older individuals display reduced ability to form memory and skewing of subset polarization. These data collectively suggest a partial breakdown in cellular quiescence.