Protective immunity to pathogens requires memory T cells that survive for many years after initial exposure to the infectious agent. The identity of the factors that influence the maintenance of naive and memory T cells in vivo remains highly sought after and is the subject of a recent study by Marc Jenkins and colleagues published in Science. They show that clone size markedly influences the survival of naive T cells and their memory-cell progeny.

To study in vivo T-cell survival, the authors first tracked polyclonal naive CD4+ T cells after adoptive transfer to congenic recipients. Although most of the two million transferred cells died within the first 2 months, with an estimated half-life of 50 days, 10% of the cells were still detectable a year after transfer. However, when one million monoclonal naive CD4+ T cells from T-cell receptor (TCR)-transgenic (DO11.10) mice were transferred to histocompatible mice, the half-life of these cells was only 12 days.

The authors proposed that the poor survival rates of monoclonal- compared with polyclonal-cell populations might be related to clone size. To enable the detection of low numbers of seeded cells following transfer of just 1,000 monoclonal cells, they developed a cell-enrichment method using magnetic beads. Of the 1,000 naive DO11.10 cells that were transferred, 10 cells survived with a half-life of 50 days and 80 cells survived with a half-life of 104 days. This is similar to the half-life of polyclonal naive CD4+ T cells, indicating that when present in physiologically appropriate numbers, naive monoclonal T cells survive longer and proliferate more.

Next, the authors showed that clone size also influences antigen-driven proliferation of naive CD4+ T cells. When high numbers (approximately 105) of naive DO11.10 cells were transferred, the cells divided fewer than 8 times and increased in number by 20-fold to a peak 3 days after injection of the cognate antigen. As observed in the absence of antigen, these cells declined rapidly, with a half-life of 11 days. However, when only 100 naive DO11.10 cells were transferred, the cells divided more than 8 times and increased in number by 200-fold after antigen exposure. Moreover, the ensuing memory population consisted of 1,500 cells with an average half-life of 46 days. So, like naive cells, memory cells benefited from a low initial clone size.

To explain these results, the authors suggest that individual CD4+ T-cell clones compete for TCR recognition of the limiting peptide–MHC-class-II ligand, rather than for a survival factor such as interleukin-7. This intraclonal competition among naive T cells might maximize both the diversity of the T-cell repertoire and the longevity of memory cells generated from this repertoire.