Signaling via the IL-2 and IL-7 Receptors from the Membrane to the Nucleus (original) (raw)

  1. W.J. LEONARD,
  2. K. IMADA,
  3. H. NAKAJIMA,
  4. A. PUEL,
  5. E. SOLDAINI, and
  6. S. JOHN
  7. Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1674

Excerpt

The interleukin 2 (IL-2) receptor consists of threechains, IL-2Rα, IL-2Rβ, and the common cytokine receptor γ chain, γc. IL-2Rβ is also shared by the IL-15 receptor, whereas γc is also a component of the receptors forIL-4, IL-7, IL-9, and IL-15. We previously demonstratedthat mutations in γc result in X-linked severe combinedimmunodeficiency (XSCID) in humans, a disease characterized by defective T- and NK-cell development butnormal B-cell development (T–NK–B+ SCID). Correspondingly, mutations in Jak3, the Janus family tyrosinekinase that interacts with γc, result in a clinical syndromeindistinguishable from XSCID except that it is an autosomal recessive disease. Based on available data fromknockout models, we hypothesized that defective IL-7signaling might explain the T-cell defect but not the NKcell defect in XSCID and Jak3 deficiency, and we haveidentified patients with T–NK+B+ SCID resulting frommutations in the IL7R gene. Interestingly, these patientshave normal B-cell development, in contrast to Il7r–/–mice. IL-2 and IL-7 signal in part via the Jak-STAT pathway; both cytokines activate Jak1 and Jak3 kinases, andStat3, Stat5a, and Stat5b are the STAT proteins that areactivated. The IL-2Rβ and IL-7Rα cytoplasmic domainsshare similar tyrosine-based motifs that mediate Stat5 activation. An important Stat5-dependent effect of IL-2 isto augment IL-2Rα expression, a process essential formaintaining high-affinity receptors and optimal sensitivity to IL-2. Interestingly, analysis of Stat5a–/– andStat5b–/– mice has revealed that defective expression ofeither Stat5 protein results in diminished IL-2-inducedup-regulation of the IL-2Rα chain. Whereas IL-2-dependent proliferation can be substantially normalized inStat5a–/– mice by high concentrations of IL-2, this is notthe case in Stat5b–/– mice. Moreover, the Stat5b–/– micehave a marked defect in natural killer cell cytolytic activity. The role of Stat5 proteins for IL-2Rα induction is explained by the presence of an IL-2 response element inthe IL-2Rα 5′ regulatory region that contains tandemconsensus and non-consensus GAS motifs as well as anElf-1 binding site. We have demonstrated that the tandemGAS motifs cooperatively bind to Stat5 tetramers andthat prevention of tetramerization by mutation of Trp-37in the Stat5a or Stat5b amino domains dramatically lowers activation of this response element. Thus, IL-2 signalsvia Stat5 proteins, and one key target for activated Stat5proteins is a component of the receptor itself, whose expression can further promote sensitivity to IL-2. Our results underscore the importance of tetramerization as amechanism for augmenting the avidity of Stat5–DNA interactions that allow Stat5 to activate a promoter withtandemly linked low-affinity GAS motifs. In this paper,we summarize recent findings on a novel form of SCID,on the distinctive phenotypes of Stat5a–/– and Stat5b–/–mice, and on the significance of Stat5 tetramerization inregulating Stat5-mediated gene expression...