Aging and T-cell diversity

Abstract

Naïve and memory CD4 and CD8 T cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4 T cells through the 7th decade of life, but eventually and abruptly fail at about the age of 75 years. In contrast, the CD8 T cell compartment is more unstable, with progressive diminution of naïve T cells and increasing loss of diversity during mid adulthood. Vaccination strategies need to aim at developing a broad repertoire of memory T cells before the critical time period when the naïve CD4 T-cell repertoire collapses. Research efforts need to aim at understanding T-cell homeostatic control mechanisms to ultimately expand the time period of repertoire stability.

Figure 1. CD8 T cells lose the naïve T-cell compartment more rapidly than CD4 T cells

Peripheral blood mononuclear cells were examined by flow cytometry for the expression of CD4, CD8, CD45RA and CCR7, and the fractions of naïve CD4 and CD8 T cells were determined.

Figure 2. Contraction of naïve CD4 T-cell repertoire diversity with age

A schematic overview of the experimental design is shown (A). CD4 naïve T cells were purified and divided into three samples of 500,000 cells each. cDNA of each sample was amplified with T-cell receptor BV8 and BJ2S5 primers and cloned using the TOPO TA Cloning Kit (Invitrogen). The amplified product of sample 1 was reamplified with internal primers to generate a short polyclonal probe representing the N-D-N sequences of sample 1. Bacterial colonies from all three samples were hybridized with the probe, and the fractions of hybridizing colonies were determined. Results from three individuals aged 20 to 30 years and older than 75 years are shown in Figure 2B. The high degree of cross-hybridization in the elderly population indicated a lack of T-cell receptor diversity. Reprinted with permission from (Naylor et al., 2005).

Figure 2. Contraction of naïve CD4 T-cell repertoire diversity with age

A schematic overview of the experimental design is shown (A). CD4 naïve T cells were purified and divided into three samples of 500,000 cells each. cDNA of each sample was amplified with T-cell receptor BV8 and BJ2S5 primers and cloned using the TOPO TA Cloning Kit (Invitrogen). The amplified product of sample 1 was reamplified with internal primers to generate a short polyclonal probe representing the N-D-N sequences of sample 1. Bacterial colonies from all three samples were hybridized with the probe, and the fractions of hybridizing colonies were determined. Results from three individuals aged 20 to 30 years and older than 75 years are shown in Figure 2B. The high degree of cross-hybridization in the elderly population indicated a lack of T-cell receptor diversity. Reprinted with permission from (Naylor et al., 2005).

Figure 3. The age period between 65 and 75 years is critical for CD4 T-cell repertoire contraction

T-cell receptor sequences were identified in a sample of naïve CD4 T cells, and their frequencies were determined in an independent sample from the same individual by limiting dilution followed by BV-BJ amplification and hybridization for N-D-N sequences as described (Naylor et al., 2005; Wagner et al., 1998). Low frequencies of the given T-cell receptor sequences indicate a highly diverse repertoire. The results show that contraction of naïve CD4 T-cell diversity with age is a non-linear process abruptly occurring between the ages of 65 and 75. Modified from (Naylor et al., 2005) with permission.