In T cell-deficient conditions, naïve T cells undergo spontaneous “homeostatic” proliferation in response to contact with self-MHC/peptide ligands. With the aid of an in vitro system, we show here that homeostatic proliferation is also cytokine-dependent. The cytokines IL-4, IL-7, and IL-15 enhanced homeostatic proliferation of naïve T cells in vitro. Of these cytokines, only IL-7 was found to be critical; thus, naïve T cells underwent homeostatic proliferation in IL-4− and IL-15− hosts but proliferated minimally in IL-7− hosts. In addition to homeostatic proliferation, the prolonged survival of naïve T cells requires IL-7. Thus, naïve T cells disappeared gradually over a 1-month period upon adoptive transfer into IL-7− hosts. These findings indicate that naïve T cells depend on IL-7 for survival and homeostatic proliferation.

After their development in the thymus, mature T cells are maintained in the periphery by two sets of survival signals, namely TCR signals from contact with self-peptide/MHC ligands and the cytokine receptor signals from binding IL-7 and IL-15. These signals cooperate to maximize the utility of finite resources to support a diverse pool of mature T cells. It is becoming increasingly clear that multiple mechanisms exist to regulate expression of IL-7R at the transcriptional and post-translational levels. The interplay between TCR signals and IL-7R signals are also important in regulation of IL-7R expression. This review will focus on regulation of T cell homeostasis by IL-7R signaling, with an emphasis on the cross talk between signals from TCR and IL-7R.

In the course of an immune response to an infectious microbe, pathogen-specific naïve CD4+ T cells proliferate extensively and differentiate into effector cells. Most of these cells die rapidly, but a small fraction of effector cells persist as memory cells to confer enhanced protection against the same pathogen. Recent advances indicate that strong TCR stimulation during the primary response is essential for the generation of long-lived memory CD4+ T cells. Memory cells appear to be derived equally from all subsets of effector cells, and memory cells can also acquire additional functional capabilities during the secondary response. Resting memory CD4+ cells are dependent on signals from contact with IL-7 and IL-15, but not MHC class II, for their survival and intermittent homeostatic proliferation.

The peripheral mature T cell pool is regulated by complex homeostatic mechanisms. Naive T cells are maintained by interleukin-7 (IL-7) and T cell receptor (TCR) signaling from contact with major histocompatibility complex (MHC), which sustain expression of antiapoptotic molecules and allow the cells to survive in interphase. Competition for these ligands declines when T cell numbers are reduced and causes residual naive T cells to proliferate and differentiate into memory-like cells. This memory cell population is thus heterogeneous and comprised of cells derived from responses to both foreign and self-antigens. Typical memory cells are kept alive and induced to divide intermittently by a mixture of IL-7 and IL-15. This review highlights recent advances in how naive and memory T cell homeostasis is regulated.