Requirement for an initial signal from the membrane-proximal region of the interleukin 2 receptor γ _c chain for Janus kinase activation leading to T cell proliferation

Abstract

The interleukin 2 receptor (IL-2R) generates proliferative signals in T lymphocytes by ligand-induced heterodimerization of two chains, IL-2R␤ and ␥ c , which associate with the tyrosine kinases Jak1 and Jak3, respectively. Genetic and molecular studies have demonstrated that Jak3 is essential for mitogenic signaling by the ␥ c chain; because it is also the only molecule known to associate with ␥ c , we speculated that Jak3 might be sufficient for signaling by this chain. Therefore, fusion proteins were constructed in which all or part of the cytoplasmic domain of ␥ c was replaced by Jak3. Signaling was evaluated in the IL-2-dependent T cell line CTLL-2 using chimeric IL-2R␤ and ␥ c chains that bind and are activated by the cytokine granulocyte-macrophage colony-stimulating factor. Chimeric

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

“…Since it has previously been shown that a covalently linked JAK3 molecule can functionally replace the cytoplasmic domain of CD132, the role of CD132 in IL-2R signaling appears to be restricted to the recruitment of JAK3 [13]. By contrast, CD122 provides essential docking sites for at least two major downstream signaling mediators, the adaptor protein Shc and the transcription factor STAT5.…”

“…CD122 is common to both the IL-2R and IL-15R, with each receptor having a unique a chain that defines receptor specificity (IL-2Ra and IL-15Ra, respectively). Unlike CD122, the role of CD25 appears to be confined to increasing binding affinity (KD *10 -9 -10 -11 M) and it is postulated that the short cytoplasmic domain is unlikely to contribute to signaling [13][14][15][16][17][18].…”

Enhanced signaling through the IL-2 receptor in CD8+T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8+T cells rather than promotion of cell death

“…Therefore, we examined the effect of enhanced, regulated IL-2R signaling during CD8 ϩ T cell responses by generating Tg mice that express a chimeric GMIL2R under the control of a CD8 enhancer͞ promoter element, as this model mimics the effects of increased availability of IL-2 to trigger the IL-2R selectively in responding CD8 ϩ T cells. In particular, the native GM-CSF receptor and IL-2R have nearly identical K d (Ϸ30 pM) as well as on͞off rates and t 1/2 values of ligand release (29,30), and ligand binding by the GMIL2R transduces a signal that is indistinguishable from the native IL-2R kinetically and functionally (31)(32)(33).…”

The IL-2 Receptor Promotes Lymphocyte Proliferation and Induction of the c-myc, bcl-2, and bcl-x Genes Through the trans-Activation Domain of Stat5

“…Expression vectors encoding the chimeric ␣␥-and ␤␤-chains (formerly denoted GM␣/2␥ and GM␤/2␤) under the control of the human ␤-actin promoter have been described previously (2,9,14,41). Mutants of ␤␤ were generated by annealing sense and antisense oligonucleotides encoding novel C-terminal sequences for ␤␤ and/or premature stop codons, and cloning overhanging ends of these annealed primers between a unique AflII site in the cytoplasmic domain of ␤␤ and a unique XbaI site immediately 3Ј to the stop codon of ␤␤.…”

“…␥c contributes to proliferative signaling by recruiting the tyrosine kinase Jak3 (4 -8), the activation of which also requires a membrane-proximal S region of IL-2R␤ (9,10). Additionally, at least one of three cytoplasmic tyrosine phosphorylation sites (Tyr 338 , Tyr 393 , or Tyr 510 ) distal to the S region on IL-2R␤ must be present for proliferation, suggesting that obligate mitogenic signaling molecules interact with these phosphotyrosines (11,12).…”