doi:10.1016/j.imlet.2007.08.005 
Copyright © 2007 Elsevier B.V. All rights reserved.
Review
Interleukin-2 receptor signaling in regulatory T cell development and homeostasis
Matthew A. Burchilla, Jianying Yanga, Kieng B. Vanga and Michael A. Farrar
, a, 
aCenter for Immunology, The Cancer Center, Department of Laboratory Medicine and Pathology, University of Minnesota, 312 Church Street SE, 6-116 Nils Hasselmo Hall, Minneapolis, MN 55455, USA
Received 26 March 2007;
revised 17 August 2007;
accepted 21 August 2007.
Available online 14 September 2007.
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Abstract
Interleukin-2 (IL2) was initially identified from supernatants of activated lymphocytes over 30 years ago. In the ensuing 15 years, the cDNAs for both IL2 and the three chains of the interleukin-2 receptor (IL2R) were cloned. Subsequently, many of the downstream biochemical pathways activated by the IL2 receptor complex were identified and the structure of IL2 bound to this tripartite receptor complex was solved. Thus, we now have a very good understanding of how each chain contributes to high affinity IL2 binding and signal transduction. In contrast, over the past 30 years the role that IL2 plays in regulating lymphocyte function has involved many surprising twists and turns. For example, IL2 has been shown, paradoxically, to regulate both lymphocyte proliferation and lymphocyte death. In this review, we briefly outline the original findings suggesting a role for IL2 as a T cell growth factor, as well as subsequent studies pointing to its function as an initiator of activation-induced cell death, but then focus on the newly appreciated role for IL2 and IL2R signaling in the development and homeostasis of regulatory T cells.
Keywords: Regulatory T cell; Interleukin-2; Signal transduction; Development; Homeostasis
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Fig. 1. Model of cytokine-dependent Treg development and homeostasis. In the thymus, IL2 plays the predominant role in driving Treg development. In the absence of IL2, IL15 is sufficient for regulatory T cell development. Other γc-dependent cytokines such as IL7 may play a minor role in this process and most likely account for the few Tregs found in IL2Rβ−/− mice as compared to γc−/− mice in which Tregs are absent. In the spleen of wild type mice, IL2-dependent signals lead to the downregulation of both the IL7Rα and IL15Rα chains. This renders mature Tregs primarily dependent on IL2 for their survival and expansion. In contrast, in IL2−/− mice, IL15Rα and IL7Rα remain expressed at high levels and allow for survival of mature Tregs. Likewise, under lymphopenic conditions, such as occurs upon introduction of Tregs into rag2−/− mice, Tregs do survive and expand. This most likely occurs due to the absence of other T cell subsets thereby leading to increased amounts of available IL15 and IL7 that can stimulate Treg survival despite lower expression of IL15Rα and IL7Rα receptors by those cells. In addition, the absence of IL2 signals may lead to re-expression of the IL15Rα and IL7Rα rendering these cells more sensitive to IL15 and IL7.
Fig. 2. Signaling components of the IL2 receptor complex. The IL2R is composed of three distinct subunits—IL2Rα, IL2Rβ, and IL2Rγ. The IL2Rβ-chain consists of three previously identified signaling domains, the A-, H-, and S-regions. The tyrosine-containing A and H regions are labeled, while the JAK1 binding domain or S-region is shaded in gray. Phosphorylation of Tyr-338 in the A region recruits the adaptor protein SHC; SHC then binds Grb2 and Gab2, leading to activation of the Ras-Raf-MAPK and PI3K/Akt signaling pathways, respectively. Phosphorylation of Tyr-392 and Tyr-510 in the H region recruits STAT5 and leads to its activation; in the absence of these two tyrosine residues Tyr-338 can also induce STAT5 activation.
Fig. 3. STAT binding motifs in the murine foxp3 gene. The murine foxp3 gene locus contains many motifs to which activated STAT molecules can bind. Black boxes represent exons while vertical lines represent consensus STAT binding motifs. The three closely linked sites (separated by 7 bp) in the promoter and the three sites labeled intronic are conserved across species.
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