Naive T cell maintenance and function in human aging

Abstract

In studies of immune aging, naive T cells frequently take center stage. Describing the complexity of the human naive T cell repertoire remains a daunting task; however, emerging data suggest that homeostatic mechanisms are robust enough to maintain a large and diverse CD4 T cell repertoire with age. Compartment shrinkage and clonal expansions are challenges for naive CD8 T cells. In addition to population aspects, identification of potentially targetable cellular defects is receiving renewed interest. The last decade has seen remarkable progress in identifying genetic and biochemical pathways that are pertinent for aging in general and that are instructive to understand naive T cell dysfunction. One hallmark sets naive T cell aging apart from most other tissues except stem cells: they initiate but do not complete differentiation programs toward memory cells. Maintaining quiescence and avoiding differentiation may be the ultimate challenge to maintain the functions unique for naive T cells.

Figure 1. Naïve T cell homeostasis and age

Thymic T cell regeneration is quantitatively irrelevant throughout adult life and homeostatic proliferation is responsible for maintaining the size of the naïve T cell compartment. While only thymic T cell generation can add novel naïve T cells and enrich diversity, homeostatic T cell proliferation can sustain the richness of the TCR repertoire (i.e. the total number of T cells with different TCR sequences), while peripheral selection during homeostatic proliferation may result in increasing unevenness, i.e., increasing inequalities in clonal sizes and clonal expansions of selected few clones. Age-associated changes in these metrics between CD4 and CD8 T cells of young (<35 years) and older (65–80 year-old) healthy adults are illustrated.