"In the structure of the quaternary ectodomain complex as visualized at a resolution of 2.3 angstroms, the binding of IL-2Ralpha to IL-2 stabilizes a secondary binding site for presentation to IL-2Rbeta."

"the binding of IL-2Ralpha to IL-2 stabilizes a secondary binding site for presentation to IL-2Rbeta. gammac is then recruited to the composite surface formed by the IL-2/IL-2Rbeta complex."

"gammac is then recruited to the composite surface formed by the IL-2/IL-2Rbeta complex. Consistent with its role as a shared receptor for IL-4, IL-7, IL-9, IL-15, and IL-21, gammac forms degenerate contacts with IL-2."

"Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 A resolution."

"The IL-2R alpha subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2R alpha with IL-2 at the cell surface."

"Surprisingly, IL-2R alpha makes no contacts with IL-2R beta or gamma(c), and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2R alpha to deliver IL-2 to the signaling complex and act as regulator of signal transduction."

"The quaternary structure is consistent with a stepwise assembly from IL-2/IL-2R alpha to IL-2/IL-2R alpha/IL-2R beta to IL-2/IL-2R alpha/IL-2R beta/gamma(c)."

"a high-affinity small molecule, SP4206 (Kd approximately 70 nM), was found to block binding of the IL-2alpha receptor (IL-2Ralpha) to IL-2 (Kd approximately 10 nM)."

"Mutational studies show that SP4206 targets virtually the same critical "hot-spot" residues on IL-2 that drive binding of IL-2Ralpha."

"our studies suggest that precise structural mimics of receptors are not required for high-affinity binding of small molecules, and they show that there are multiple solutions to tight binding at shared and adaptive hot spots."

"we eliminated the functional requirement of IL-2 for CD25 expression by engineering an IL-2 'superkine' (also called super-2) with increased binding affinity for IL-2Rbeta."

"Naive T cells express only a low density of IL-2Rbeta and IL-2Rgamma, and are therefore relatively insensitive to IL-2, but acquire sensitivity after CD25 expression, which captures the cytokine and presents it to IL-2Rbeta and IL-2Rgamma."

"On CD25- YT-1 cells, the EC50 of H9 and D10 were decreased over 10-fold (EC50 = 2.5 and 1.8 ng/mL, respectively) compared to IL-2 (EC50 = 39 ng/mL)"

"On CD25+ YT-1 cells, the EC50 of IL-2 decreased over 50-fold relative to CD25- YT-1 cells, from 39 to 0.66 ng/mL"

"The patient was homozygous for a c.497G>A transition in exon 4, leading to an amino acid substitution at codon 166 (S166N) of the protein."

"The chronic effect of this mutation led to the development of progressive manifestations of both autoimmunity, such as enteropathy, erythrodermia and severe alopecia, and immunodeficiency with chronic CMV infection."

"In conclusion, we show that CD25 expression is required to maintain immune homeostasis, and CD25 deficiency is a distinct immunological disease that leads to both an autoimmune and immunodeficiency syndrome that clinically resembles IPEX syndrome."

"CD25 null FOXP3+ Tregs from the patient were still the first to respond to IL-2 (in vitro) albeit at higher concentrations than required by healthy subject Tregs."

"CD25 deficiency altered the hierarchical signaling in response to IL-2 in favor of CD8+ T cells over the CD4+ T cells, contrary to what is observed in healthy subjects."

"IL-2 consumption by FOXP3+ Tregs is a critical event to maintain the homeostasis of the immune system, and the loss of CD25 surface expression by FOXP3+ Tregs in CD25 deficient patients is likely a contributing factor in the preferential CD8+ T cell proliferation, which are the mediators of autoimmunity."

"The human high-affinity receptor for interleukin 2 (IL-2) has been proposed as being a membrane complex composed of at least two distinct polypeptide chains: p55 (alpha chain), recognized by the anti-Tac monoclonal antibody (mAb), and p75 (beta chain), both of which are capable of binding IL-2."

"Whereas the alpha chain itself has been shown to be nonfunctional, the beta chain appears to be pivotal in the IL-2 signal transduction"

"These results clearly indicate that the beta chain is an indispensable component to the high-affinity IL-2 receptor and is responsible for the IL-2 signal transduction."

"High-affinity IL-2 binding was completely abolished by Mik-beta 1."

"The cell surface density of high-affinity membrane receptors for the T-lymphocytotrophic hormone interleukin 2 (IL-2) determines the rate of T-cell-cycle progression."

"Addition of homogeneous immunoaffinity-purified IL-2 to cell populations that expressed equivalent IL-2 and anti-Tac binding sites resulted in a time- and temperature-dependent 8- to 10-fold enhancement of Tac epitope expression and, simultaneously, a 20-30% diminishment of detectable high-affinity IL-2 binding sites."

"IL-2-receptor interactions actually promote the loss of IL-2 responsiveness by diminishing the density of high-affinity binding sites at the time that Tac antigen levels are increased."

"We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2."

"Profound cellular immunodeficiency occurs as the result of mutations in proteins involved in both the differentiation and function of mature lymphoid cells."

"This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development."

"Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation."

"CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2."