IL-2 receptor: Difference between revisions

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{{protein
{{infobox protein
|Name=interleukin 2 receptor, alpha
|Name= [[IL2RA|interleukin 2 receptor, alpha chain]]
|caption=
|caption=
|image=
| image = Protein_IL2RA_PDB_1z92.png
| image_source = [[Protein Data Bank|PDB]] rendering based on 1z92.
|width=
|width=
|HGNCid=6008
|HGNCid=6008
|Symbol=IL2RA
|Symbol=[[IL2RA]]
|AltSymbols=IL2R CD25
|AltSymbols=IL2R CD25
|EntrezGene=3559
|EntrezGene=3559
Line 18: Line 19:
|LocusSupplementaryData=
|LocusSupplementaryData=
}}
}}
{{protein
{{infobox protein
|Name=interleukin 2 receptor, beta
|Name= [[IL2RB|interleukin 2 receptor, beta chain]]
|caption=
|caption=
|image=
| image = Protein_IL2RB_PDB_2b5i.png
| image_source = [[Protein Data Bank|PDB]] rendering based on 2b5i.
|width=
|width=
|HGNCid=6009
|HGNCid=6009
|Symbol=IL2RB
|Symbol=[[IL2RB]]
|AltSymbols=CD122
|AltSymbols=CD122
|EntrezGene=3560
|EntrezGene=3560
Line 37: Line 39:
|LocusSupplementaryData=
|LocusSupplementaryData=
}}
}}
{{protein
{{infobox protein
|Name=interleukin 2 receptor, gamma ([[severe combined immunodeficiency]])
|Name= [[IL2RG|interleukin 2 receptor, gamma chain]] ([[severe combined immunodeficiency]])
|caption=
|caption=
|image=
|image = Protein_IL2RG_PDB_2b5i.png
|image_source = Crystallographic structure of [[Interleukin 2|IL-2]] (center [[alpha helix|alpha helices]]) complexed with the common gamma chain (IL2RG; 10 O'Clock to 1 O'Clock), [[IL2RA]]  (4 O'Clock), and [[IL2RB]] (7 O'Clock to 9 O'Clock).  Each protein is individually rainbow colored ([[N-terminus]] = blue, [[C-terminus]] = red).<ref name="pmid16293754">{{PDB|2B5I}}{{cite journal |vauthors=Wang X, Rickert M, Garcia KC | title = Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors | journal = Science | volume = 310 | issue = 5751 | pages = 1159–63 | year = 2005 | pmid = 16293754 | doi = 10.1126/science.1117893 | url = | issn = }}</ref>
|width=
|width=
|HGNCid=6010
|HGNCid=6010
|Symbol=IL2RG
|Symbol=[[IL2RG]]
|AltSymbols=SCIDX1, IMD4
|AltSymbols=SCIDX1, IMD4, CD132
|EntrezGene=3561
|EntrezGene=3561
|OMIM=308380
|OMIM=308380
Line 57: Line 60:
}}
}}


The '''interleukin-2 receptor''' ('''IL-2R''') is a [[trimer (biochemistry)|heterotrimeric]] protein expressed on the surface of certain immune cells, such as [[lymphocyte]]s, that binds and responds to a [[cytokine]] called [[interleukin 2|IL-2]].


==Overview==
== Composition ==
The '''interleukin-2 receptor''' (IL-2R) is [[trimer (biochemistry)|heterotrimeric]] protein expressed on the surface of certain immune cells, such as [[lymphocyte]]s, that binds and responds to a [[cytokine]] called [[interleukin 2]].  Three protein chains (α, β and γ) are [[non-covalent|non-covelently]] associated to form the IL-2R.  The α and β chains are involved in binding IL-2, while [[signal transduction]] following cytokine interaction is carried out by the γ-chain, along with the β subunit.  The β and γ chains of the IL-2R are members of the [[type I cytokine receptor]] family.


   
IL-2 binds to the IL-2 receptor, which has three forms, generated by different combinations of three different proteins, often referred to as "chains": [[IL2RA|α (alpha)]] (also called IL-2Rα, CD25, or Tac antigen), [[IL2RB|β (beta)]] (also called IL-2Rβ, or CD122), and γ (gamma) (also called IL-2Rγ, γ<sub>c</sub>, [[common gamma chain]], or CD132); these subunits are also parts of receptors for other cytokines.<ref name=Leonard>Warren J. Leonard. Type I Cytokines and Interferons and Their Receptors. Chapter 23 in Fundamental Immunology, 6th ed. Editor, William E. Paul. Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, c2008.  {{ISBN|9780781765190}}</ref>{{rp|713}} The β and γ chains of the IL-2R are members of the [[type I cytokine receptor]] family.<ref name="Liao_2011">{{cite journal |vauthors=Liao W, Lin JX, Leonard WJ | title = IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation | journal = Curr. Opin. Immunol. | volume = 23 | issue = 5 | pages = 598–604 | year = 2011 | pmid = 21889323 | pmc = 3405730 | doi = 10.1016/j.coi.2011.08.003 | url = }}</ref>
==Discovery and characterization==


The IL-2 receptor (IL-2R) was the first [[interleukin]] receptor to be described and characterized.<ref>Robb, R.J. (1981) J Exp Med 154:1455</ref> It was found to have a high affinity binding site and is expressed by antigen-activated T lymphocytes ([[T cell]]s). Radiolabeled IL-2 concentrations found to saturate these sites (e.g. 1-100 pM) were identical to those determined to promote T cell [[proliferation]]. Subsequently, the three distinct receptor chains, termed alpha (α),<ref>Leonard, WJ ''et al.'' (1982) Nature 300:267</ref> beta (β)<ref>Sharon, M. ''et al.'' (1986) Science 234:859.</ref><ref>Teshigawara, K. ''et al.'' (1987) J Exp Med 165:223</ref><ref>Tsudo, M. ''et al.'' Proc Natl. Acad. Sci. (USA) (1987) 84:4215.</ref> and gamma (γ)<ref>Takeshita, T. et.al. J Immunol. (1992) 148:2154</ref> were identified.  The high [[affinity]] of IL-2 binding is created by a rapid association rate (k = 10e7/M/s) contributed to the alpha chain, and a relatively slow dissociation rate (k' = 10e-4/s) contributed to the beta and gamma chains.<ref>Wang, HM and Smith, KA (1987) J Exp Med 66:1055</ref><ref>Johnson, K ''et al.'' (1994) Euro Cyto Netw 5:23.</ref>
== Structure-activity relationships of the IL-2/IL-2R interaction ==


==Structure-activity relationships of the IL-2/IL-2R interaction==
The three receptor chains are expressed separately and differently on various cell types and can assemble in different combinations and orders to generate low, intermediate, and high affinity IL-2 receptors.


Detailed experiments over a decade (1990s) using a rigorous reductionist approach with isolated purified receptor chains and [[Surface plasmon resonance]] revealed that the alpha chain of the IL-2R binds to the beta chain before receptor interaction with IL-2, and that the IL-2Rαβ heterodimer formed has a faster association rate and a slower dissociation rate when binding IL-2 versus either chain alone.<ref>Liparoto, S and Ciardelli, T. (1999) J Mol Rec 12:2543</ref> The gamma chain alone has a very weak affinity for IL-2 (Kd > 700 uM), but after IL-2 is bound to the αβ heterodimer, the gamma chain becomes recruited to the IL2/IL2R complex to forms a very stable [[macromolecular]] quaternary ligand/receptor complex. These data were recently confirmed and extended by energetics experiments using [[Isothermal Titration Calorimetry]] and Multi-Angle Light [[Scattering]].<ref>Rickert, M. ''et al.'' (2004) J Mol Biol 339:1115</ref>
The α chain binds IL-2 with low affinity, the combination of β and γ together form a complex that binds IL-2 with intermediate affinity, primarily on [[memory T cells]] and [[NK cells]]; and all three receptor chains form a complex that binds IL-2 with high affinity (Kd ~ 10<sup>−11</sup> M) on activated [[T cells]] and [[regulatory T cells]] The intermediate and high affinity receptor forms are functional and cause changes in the cell when IL-2 binds to them.<ref name="Liao_2011"/>


The 3-dimensional structure of the three IL-2R chains binding IL-2 was determined by crystallization of the complex followed by X-ray diffraction.<ref>Wang, X ''et al.'' (2005) Science 310:1159</ref><ref>Stauber, D. ''et al.'' (2006) Proc Natl Acad Sci (USA) 103:2788</ref> The sites on the IL-2 molecule that interact with the three receptor chains do not overlap, except for a small but significant region. The IL-2 molecule is comprised of 4 antiparallel [[alpha helix|alpha helices]] and it is held between the beta and gamma chains, which converge to form a Y shape; IL-2 is held in the fork of the Y. The other side of the IL-2 molecule binds to the IL-2R alpha chain. The alpha chain itself does not contact either beta or gamma chain of the IL-2R. Following the binding of IL-2, the beta chain undergoes a conformational change that evidently increases its affinity for the gamma chain, thereby attracting it to form a stable quaternary molecular complex.
The structure of the stable complex formed when IL-2 binds to the high affinity receptor has been determined using [[X-ray crystallography]]. The structure supports a model wherein IL-2 initially binds to the α chain, then the β is recruited, and finally γ.<ref name="Liao_2011"/><ref name=Malek_2010>{{cite journal |vauthors=Malek TR, Castro I | title = Interleukin-2 receptor signaling: at the interface between tolerance and immunity | journal = Immunity | volume = 33 | issue = 2 | pages = 153–65 | year = 2010 | pmid = 20732639 | pmc = 2946796 | doi = 10.1016/j.immuni.2010.08.004 }}</ref><ref>Metz A, Ciglia E, Gohlke H. Modulating protein-protein interactions: from structural determinants of binding to druggability prediction to application. Curr Pharm Des. 2012;18(30):4630-47. {{PMID|22650257}}</ref>


==Signaling through the IL-2R==
==Signaling==


The three IL-2 receptor chains span the [[cell membrane]] and extend into the cell, thereby delivering biochemical signals to the cell interior. The alpha chain does not participate in signaling, but the beta chain is complexed with an [[enzyme]] called [[JAK|Janus kinase 1]] (JAK1), that is capable of adding phosphate groups to molecules.  Similarly the gamma chain  complexes with another [[tyrosine kinase]] called [[JAK]]3.<ref>Nelson, B. ''et al.'' (1994) Nature 369:333</ref><ref>Russel, S., ''et al.'' (1994) Science 266: 1042</ref> These enzymes are activated by IL-2 binding (or IL-15 binding)to the external domains of the IL-2R. As a consequence, three intracellular signaling pathways are initiated, the [[MAPK/ERK pathway|MAP kinase pathway]],<ref>Zumuidzinas, N. ''et al.'' (1991) Mol Cell Biol 11:2794</ref> the [[Phosphoinositide 3-kinase]] (PI3K) pathway,<ref>Moon, J. ''et al.'' (2004) J Biol Chem 279:5520</ref> and the [[JAK-STAT pathway]].<ref name="Morriggl 1999">Morriggl, R. ''et al.'' (1999) Immunity 10: 249</ref>
The three IL-2 receptor chains span the [[cell membrane]] and extend into the cell, thereby [[signal transduction|delivering biochemical signals to the cell interior]]. The alpha chain does not participate in signaling, but the beta chain is complexed with an [[enzyme]] called [[Janus kinase 1]] (JAK1), that is capable of adding phosphate groups to molecules.  Similarly the gamma chain  complexes with another [[tyrosine kinase]] called [[Janus kinase|JAK3]]. These enzymes are activated by IL-2 binding to the external domains of the IL-2R. As a consequence, three intracellular signaling pathways are initiated, the [[MAPK/ERK pathway|MAP kinase pathway]], the [[Phosphoinositide 3-kinase]] (PI3K) pathway, and the [[JAK-STAT pathway]].<ref name="Liao_2011"/><ref name=Malek_2010/>


==IL-2/IL-2R stimulation of T cell proliferation==
Once IL-2 binds to the high affinity receptor, the complex is rapidly internalized and has only a short time to signal.  IL-2, IL-2Rβ, and γ<sub>c</sub> are rapidly degraded, but IL-2Rα is recycled to the cell surface. Thus, the concentration of IL-2 and its receptor available determines the tempo, magnitude and extent of T cell immune responses.<ref name="Liao_2011"/><ref name=Malek_2010/>


Once IL-2 binds to the external domains of the IL-2R and the cytoplasmic domains are engaged, signaling continues until the IL-2/IL-2R complex is internalized and degraded. However, each cell only decides to make the irrevocable commitment to replicate its DNA and undergo mitosis and [[cytokinesis]] when a critical number of IL-2Rs have been triggered.<ref>Cantrell, DA and Smith, KA (1984) Science 224:1312</ref> Given that the half-time for internalization of IL-2 occupied IL-2Rs is ~ 15 minutes,<ref>Smith, KA (1989) Ann Rev Cell Biol 5:397</ref> it is possible to calculate the number of triggered IL-2Rs necessary. Thus, the critical number of triggered IL-2Rs is ~ 30,000. In as much that the mean number of high affinity IL-2Rs on antigen-activated T cells is only ~ 1,000, it appears that new receptors must be synthesized before the cell makes the quantal, all-or-none decision to  divide.<ref>Smith, KA (2004) 3:3. (2006) Cell Res. 16:11</ref> Accordingly, a mean of at least 11 hours of IL-2/IL-2R interaction are necessary before a cell decides to undergo DNA replication.
IL-2 and its receptor have key roles in key functions of the immune system, [[Central tolerance|tolerance]] and [[Immunity (medical)|immunity]], primarily via their direct effects on [[T cells]].  In the [[thymus]], where T cells mature, they prevent [[autoimmune diseases]] by promoting the [[Cellular differentiation|differentiation]] of certain immature T cells into [[regulatory T cells]], which kill off other T cells that are primed to attack normal healthy cells in the body.  IL-2/IL2R also promotes the differentiation of T cells into [[effector T cells]] and into [[memory T cells]] when the initial T cells is also stimulated by an [[antigen]], thus helping the body fight off infections.<ref name="Liao_2011"/>   Through their role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, they also have a key role in enduring [[cell-mediated immunity]].<ref name="Liao_2011"/><ref name=Malek_2010/>


Until recently, the intracellular molecules activated by the IL-2R at the cell membrane that are responsible for promoting cell cycle progression were obscure. However, early on it was shown that IL-2Rs triggered the expression of [[cyclin]] D2 and cyclin D3.<ref>Turner, J. (1993) Int Immunol. 5: 1199</ref> Now it is known that the [[STAT]]5a/b molecules activated by the IL-2R via the JAK1/3 kinases promote the transcriptional activation of the D cyclins.<ref name="Morriggl 1999"/> As well, via the activation of the PI3K pathway, an inhibitor of cyclin-D/CDK activity (p27) is targeted for degradation.<ref>Nourse, J. ''et al.'' (1994) 372:570</ref> Both of these biochemical events, as well as others activated via the IL-2R<ref>Martino, A. ''et al.'' (2001) J Immunol 166:1723</ref> ultimately promote progression through G1 of the cell cycle and through the G1 restriction point, thereby triggering the onset of DNA synthesis and replication. Recent work has uncovered an unexpected function of IL-2 that has been seen as dichotomous to its role as a T-cell growth factor: maintaining peripheral tolerance by supporting the survival and function of CD25+ CD4+ regulatory T cells.<ref name="Fehervari 2006">Fehervari, Z. ''et al.'' (2006) Trends Immunol 27:109</ref>
==Clinical implications==
Drugs that inhibit IL-2 receptors, such as [[basiliximab]] and [[daclizumab]] are used in conjunction with other drugs to prevent [[Transplant rejection|immune rejection of transplants]].<ref name=HardingerRev>Hardinger KL, Brennan DC, Klein CL.  Selection of induction therapy in kidney transplantation. Transpl Int. 2013 Jul;26(7):662-72. {{PMID|23279211}}</ref>
 
==History==
According to an immunology textbook: "IL-2 is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine, including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to the growth factors being studied by endocrinologists and biochemists".<ref name=Leonard/>{{rp|712}}
 
==See also==
[[CD25 deficiency]]


==References==
==References==
<references/>
{{reflist|30em}}


==External links==
==External links==
* {{MeshName|Interleukin-2+Receptors}}
* {{MeshName|Interleukin-2+Receptors}}


{{Immune receptors}}
{{Cytokine receptors|state=collapsed}}
{{Clusters of differentiation}}
{{Clusters of differentiation}}
{{Interleukin receptor modulators}}


[[Category:Receptors]]
[[Category:Type I cytokine receptors]]
[[Category:Cytokines]]
[[Category:Integral membrane proteins]]
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Revision as of 17:00, 9 August 2017

interleukin 2 receptor, alpha chain
File:Protein IL2RA PDB 1z92.png
Identifiers
SymbolIL2RA
Alt. symbolsIL2R CD25
Entrez3559
HUGO6008
OMIM147730
RefSeqNM_000417
UniProtP01589
Other data
LocusChr. 10 p15.1
interleukin 2 receptor, beta chain
File:Protein IL2RB PDB 2b5i.png
Identifiers
SymbolIL2RB
Alt. symbolsCD122
Entrez3560
HUGO6009
OMIM146710
RefSeqNM_000878
UniProtP14784
Other data
LocusChr. 22 q13
interleukin 2 receptor, gamma chain (severe combined immunodeficiency)
File:Protein IL2RG PDB 2b5i.png
Identifiers
SymbolIL2RG
Alt. symbolsSCIDX1, IMD4, CD132
Entrez3561
HUGO6010
OMIM308380
RefSeqNM_000206
UniProtP31785
Other data
LocusChr. X q13

The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called IL-2.

Composition

IL-2 binds to the IL-2 receptor, which has three forms, generated by different combinations of three different proteins, often referred to as "chains": α (alpha) (also called IL-2Rα, CD25, or Tac antigen), β (beta) (also called IL-2Rβ, or CD122), and γ (gamma) (also called IL-2Rγ, γc, common gamma chain, or CD132); these subunits are also parts of receptors for other cytokines.[1]:713 The β and γ chains of the IL-2R are members of the type I cytokine receptor family.[2]

Structure-activity relationships of the IL-2/IL-2R interaction

The three receptor chains are expressed separately and differently on various cell types and can assemble in different combinations and orders to generate low, intermediate, and high affinity IL-2 receptors.

The α chain binds IL-2 with low affinity, the combination of β and γ together form a complex that binds IL-2 with intermediate affinity, primarily on memory T cells and NK cells; and all three receptor chains form a complex that binds IL-2 with high affinity (Kd ~ 10−11 M) on activated T cells and regulatory T cells The intermediate and high affinity receptor forms are functional and cause changes in the cell when IL-2 binds to them.[2]

The structure of the stable complex formed when IL-2 binds to the high affinity receptor has been determined using X-ray crystallography. The structure supports a model wherein IL-2 initially binds to the α chain, then the β is recruited, and finally γ.[2][3][4]

Signaling

The three IL-2 receptor chains span the cell membrane and extend into the cell, thereby delivering biochemical signals to the cell interior. The alpha chain does not participate in signaling, but the beta chain is complexed with an enzyme called Janus kinase 1 (JAK1), that is capable of adding phosphate groups to molecules. Similarly the gamma chain complexes with another tyrosine kinase called JAK3. These enzymes are activated by IL-2 binding to the external domains of the IL-2R. As a consequence, three intracellular signaling pathways are initiated, the MAP kinase pathway, the Phosphoinositide 3-kinase (PI3K) pathway, and the JAK-STAT pathway.[2][3]

Once IL-2 binds to the high affinity receptor, the complex is rapidly internalized and has only a short time to signal. IL-2, IL-2Rβ, and γc are rapidly degraded, but IL-2Rα is recycled to the cell surface. Thus, the concentration of IL-2 and its receptor available determines the tempo, magnitude and extent of T cell immune responses.[2][3]

IL-2 and its receptor have key roles in key functions of the immune system, tolerance and immunity, primarily via their direct effects on T cells. In the thymus, where T cells mature, they prevent autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells, which kill off other T cells that are primed to attack normal healthy cells in the body. IL-2/IL2R also promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cells is also stimulated by an antigen, thus helping the body fight off infections.[2] Through their role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, they also have a key role in enduring cell-mediated immunity.[2][3]

Clinical implications

Drugs that inhibit IL-2 receptors, such as basiliximab and daclizumab are used in conjunction with other drugs to prevent immune rejection of transplants.[5]

History

According to an immunology textbook: "IL-2 is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine, including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to the growth factors being studied by endocrinologists and biochemists".[1]:712

See also

CD25 deficiency

References

  1. ↑ 1.0 1.1 Warren J. Leonard. Type I Cytokines and Interferons and Their Receptors. Chapter 23 in Fundamental Immunology, 6th ed. Editor, William E. Paul. Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, c2008. ISBN 9780781765190
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Liao W, Lin JX, Leonard WJ (2011). "IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation". Curr. Opin. Immunol. 23 (5): 598–604. doi:10.1016/j.coi.2011.08.003. PMC 3405730. PMID 21889323.
  3. ↑ 3.0 3.1 3.2 3.3 Malek TR, Castro I (2010). "Interleukin-2 receptor signaling: at the interface between tolerance and immunity". Immunity. 33 (2): 153–65. doi:10.1016/j.immuni.2010.08.004. PMC 2946796. PMID 20732639.
  4. ↑ Metz A, Ciglia E, Gohlke H. Modulating protein-protein interactions: from structural determinants of binding to druggability prediction to application. Curr Pharm Des. 2012;18(30):4630-47. PMID 22650257
  5. ↑ Hardinger KL, Brennan DC, Klein CL. Selection of induction therapy in kidney transplantation. Transpl Int. 2013 Jul;26(7):662-72. PMID 23279211

External links

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