Much as plants compete for essential resources such as space, sunlight, water and nutrients, so peripheral T cells compete for limited growth and survival signals, which keeps the overall population size remarkably constant. The factors that regulate the size of the memory CD4+ T-cell pool have long been a mystery, but a new study shows that the answer was under our noses all along.

Different T-cell subsets depend on distinct survival signals and, in this way, competition for the same 'niche' is avoided. Interleukin-7 (IL-7) and contact with MHC class I or MHC class II molecules are thought to maintain the naive CD8+ and CD4+ T-cell pools, whereas memory CD8+ T cells require IL-7 and IL-15. But none of these factors seems to be required for the survival of memory CD4+ T cells. Benedict Seddon and colleagues decided to revisit this issue.

First, the role of T-cell receptor (TCR) signals was investigated using mice deficient in both Lck and Fyn (crucial components of TCR signalling) that carried an inducible Lck transgene. When Lck was switched on, normal memory and naive T-cell compartments were generated. When the transgene was switched off, the naive CD4+ T cells disappeared, but the memory-phenotype CD4+ T cells survived, confirming previous reports that TCR signals are not required for the survival of memory T cells.

Previous studies have also ruled out a requirement for IL-7. But, what happens when both IL-7 and TCR signals are lacking? Lck-deficient memory CD4+ T cells were transferred to lymphocyte deficient Il7−/−Rag1−/− mice. The transferred cells failed to divide and few were recovered compared with similar transfers to Il7+/+Rag1−/− mice. This shows that both IL-7 and TCR signals are involved in the maintenance of the memory T-cell pool, but when either signal is missing the other can compensate.

Further adoptive-transfer experiments showed that whereas IL-7 promoted both proliferation and cell survival, TCR signals mainly stimulated proliferation; experiments in intact mice confirmed that this holds true in the steady state.

So, in contrast to earlier assumptions, the homeostasis of memory and naive CD4+ T cells is controlled by the same factors — IL-7 and TCR signals.