Cytokines and T-cell homeostasis
Introduction
Throughout life, lymphocytes are maintained at fairly stable numbers by various homeostatic mechanisms. For mature post-thymic T cells, these mechanisms are mainly governed by cytokines. Thus, naïve T cells constantly receive low-level signals through contact with interleukin (IL)-7 and major histocompatibility complex (MHC) molecules. These signals do not induce proliferation but instead allow the cells to survive for prolonged periods in a quiescent state [1, 2, 3, 4, 5]. By contrast, memory T cells appear to maintain their numbers independently of contact with peptide–MHC complexes but are heavily dependent on signals received by cytokines. For CD8+ memory cells, both IL-15 and IL-7 are important for homeostatic background proliferation and survival, whereas CD4+ memory cells rely mainly on IL-7 (Figure 1, Figure 2). Memory cells include cells that result from immunization with defined antigens as well as naturally occurring ‘memory-phenotype’ cells; these latter cells share many phenotypic and functional characteristics of antigen-specific memory cells and are probably generated in response to environmental or self antigens [1, 5].
In this article, we will review new insights into T-cell homeostasis from the recent literature, focusing on the past two years. We will attempt to integrate this new information into a framework in which multiple cytokines are central to homeostatic proliferation and survival of mature T cells.
Section snippets
Common γ chain cytokines
IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 share the common γ chain (γc) cytokine receptor and are crucial for lymphocyte generation, survival and homeostasis. Two members of this group, namely IL-7 and IL-15, play a key role in CD8+ T-cell homeostasis (Figure 1), as mentioned above. More recently, other γc cytokines, most notably IL-2, have been shown to regulate homeostasis of memory CD8+ cells under defined conditions. Thus, after IL-2 injection, enhanced IL-2 signals augment proliferation and
Common γ chain cytokines
Although IL-2 was originally described as a T-cell growth factor, the role of IL-2 had to be revised when IL-2−/− mice were found to contain above normal T-cell numbers and develop severe autoimmunity. Currently, the best-defined role of IL-2 for CD4+ cells is in the maintenance of tolerance by supporting survival of CD4+CD25+ regulatory T cells (Tregs) [43]. For naïve CD4+ cells, chimera studies showed that IL-2Rα−/− CD4+ T cells generated normal numbers of effector and memory cells in the
Conclusions
It is now becoming increasingly clear that T-cell homeostasis is influenced by multiple cytokines, which provides novel opportunities for selectively increasing the proportions of certain subsets or decreasing others. In the case of CD8+ cells, these cells can be expanded in vivo by injection of IL-2, IL-4 or IL-15, especially when complexed with specific mAbs [6••, 7, 8] or, for IL-15, with soluble IL-15Rα [49, 50] (Figure 1, Figure 2).
The influence of other cytokines such as IFNs, IL-12,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
This work was supported by a grant from the Novartis Foundation for Medicine and Biology (to OB), by a CJ Martin Fellowship from the Australian National Health and Medical Research Council (to JFP), by NIH grants (to CDS), and by NHMRC grants (to JS).
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