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interleukin 2 receptor, alpha
Symbol IL2RA
Alt. symbols IL2R CD25
Entrez 3559
HUGO 6008
OMIM 147730
RefSeq NM_000417
UniProt P01589
Other data
Locus Chr. 10 p15.1
interleukin 2 receptor, beta
Symbol IL2RB
Alt. symbols CD122
Entrez 3560
HUGO 6009
OMIM 146710
RefSeq NM_000878
UniProt P14784
Other data
Locus Chr. 22 q13
interleukin 2 receptor, gamma (severe combined immunodeficiency)
Symbol IL2RG
Alt. symbols SCIDX1, IMD4, CD132
Entrez 3561
HUGO 6010
OMIM 308380
RefSeq NM_000206
UniProt P31785
Other data
Locus Chr. 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 interleukin 2. Three protein chains (α, β and γ) are non-covalently 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.


Discovery and characterization

The IL-2 receptor (IL-2R) was the first interleukin receptor to be described and characterized by Kendall Smith and his team at Dartmouth Medical School.[1] It was found to have a high affinity binding site and is expressed by antigen-activated T lymphocytes (T cells). 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),[2] beta (β)[3][4][5] and gamma (γ)[6] were identified. The high affinity of IL-2 binding is created by a rapid association rate (k = 107/M/s) contributed by the alpha chain, and a relatively slow dissociation rate (k' = 10-4/s) contributed by the beta and gamma chains.[7][8]

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

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 can bind to the beta chain before receptor interaction with IL-2, and that the IL-2Rα/β heterodimer formed has a faster association rate and a slower dissociation rate when binding IL-2 versus either chain alone.[9] The gamma chain alone has a very weak affinity for IL-2 (Kd > 700 uM), but after IL-2 is bound to the α/β heterodimer, the gamma chain becomes recruited to the IL2/IL2R complex to form 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.[10]

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.[11][12]

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 composed of four antiparallel 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 alpha chain is called CD25.

Signaling through the IL-2R

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.[13][14] 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,[15]the Phosphoinositide 3-kinase (PI3K) pathway,[16] and the JAK-STAT pathway.[17]

IL-2/IL-2R stimulation of T cell proliferation

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.[18] Given that the half-time for internalization of IL-2 occupied IL-2Rs is ~ 15 minutes,[19] 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.[20] Accordingly, a mean of at least 11 hours of IL-2/IL-2R interaction are necessary before a cell decides to undergo DNA replication.

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.[21] Now it is known that the STAT5a/b molecules activated by the IL-2R via the JAK1/3 kinases promote the transcriptional activation of the D cyclins.[17] As well, via the activation of the PI3K pathway, an inhibitor of cyclin-D/CDK activity (p27) is targeted for degradation.[22] Both of these biochemical events, as well as others activated via the IL-2R[23]ultimately promote progression through G1 of the cell cycle and through the G1 restriction point, thereby triggering the onset of DNA synthesis and replication.

The IL2R also signals negative feedback loops that function to inhibitIL-2 gene expression. These loops either shut down signaling via the T cell antigen receptor by activating the expression of CTLA-4, or by activating the expression of FOXP3, which as a negative regulator of IL-2 transcription operates at the level of the IL-2 promoter.

Other recent data indicate that T cells that express FOXP3 can suppress other T cells by binding IL-2 via the high affinity IL-2R, and followed by internalization of the quaternary IL-2/IL-2R complex, degrade IL-2. Thus, the concentration of IL-2 available determines the tempo, magnitude and extent of T cell immune responses.


  1. ^ Robb RJ, Munck A, Smith KA (1981). "T cell growth factor receptors. Quantitation, specificity, and biological relevance". J. Exp. Med. 154 (5): 1455–74. doi:10.1084/jem.154.5.1455. PMID 6975347.  
  2. ^ Leonard WJ, Depper JM, Uchiyama T, Smith KA, Waldmann TA, Greene WC (1982). "A monoclonal antibody that appears to recognize the receptor for human T-cell growth factor; partial characterization of the receptor". Nature 300 (5889): 267–9. doi:10.1038/300267a0. PMID 6815536.  
  3. ^ Sharon M, Klausner RD, Cullen BR, Chizzonite R, Leonard WJ (1986). "Novel interleukin-2 receptor subunit detected by cross-linking under high-affinity conditions". Science 234 (4778): 859–63. doi:10.1126/science.3095922. PMID 3095922.  
  4. ^ Teshigawara K, Wang HM, Kato K, Smith KA (1987). "Interleukin 2 high-affinity receptor expression requires two distinct binding proteins". J. Exp. Med. 165 (1): 223–38. doi:10.1084/jem.165.1.223. PMID 3098894.  
  5. ^ Tsudo M, Kozak RW, Goldman CK, Waldmann TA (1987). "Contribution of a p75 interleukin 2 binding peptide to a high-affinity interleukin 2 receptor complex". Proc. Natl. Acad. Sci. U.S.A. 84 (12): 4215–8. doi:10.1073/pnas.84.12.4215. PMID 3108887.  
  6. ^ Takeshita T, Ohtani K, Asao H, Kumaki S, Nakamura M, Sugamura K (1992). "An associated molecule, p64, with IL-2 receptor beta chain. Its possible involvement in the formation of the functional intermediate-affinity IL-2 receptor complex". J. Immunol. 148 (7): 2154–8. PMID 1545122.  
  7. ^ Wang HM, Smith KA (1987). "The interleukin 2 receptor. Functional consequences of its bimolecular structure". J. Exp. Med. 166 (4): 1055–69. doi:10.1084/jem.166.4.1055. PMID 3116143.  
  8. ^ Johnson K, Choi Y, Wu Z, Ciardelli T, Granzow R, Whalen C, Sana T, Pardee G, Smith K, Creasey A (1994). "Soluble IL-2 receptor beta and gamma subunits: ligand binding and cooperativity". Eur. Cytokine Netw. 5 (1): 23–34. PMID 8049354.  
  9. ^ Liparoto SF, Ciardelli TL (1999). "Biosensor analysis of the interleukin-2 receptor complex". J. Mol. Recognit. 12 (5): 316–21. doi:10.1002/(SICI)1099-1352(199909/10)12:5<316::AID-JMR468>3.0.CO;2-1. PMID 10556880.  
  10. ^ Rickert M, Boulanger MJ, Goriatcheva N, Garcia KC (2004). "Compensatory energetic mechanisms mediating the assembly of signaling complexes between interleukin-2 and its alpha, beta, and gamma(c) receptors". J. Mol. Biol. 339 (5): 1115–28. doi:10.1016/j.jmb.2004.04.038. PMID 15178252.  
  11. ^ Wang X, Rickert M, Garcia KC (2005). "Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors". Science 310 (5751): 1159–63. doi:10.1126/science.1117893. PMID 16293754.  
  12. ^ Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA (2006). "Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor". Proc. Natl. Acad. Sci. U.S.A. 103 (8): 2788–93. doi:10.1073/pnas.0511161103. PMID 16477002.  
  13. ^ Nelson BH, Lord JD, Greenberg PD (1994). "Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation". Nature 369 (6478): 333–6. doi:10.1038/369333a0. PMID 7514277.  
  14. ^ Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O (1994). "Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID". Science 266 (5187): 1042–5. doi:10.1126/science.7973658. PMID 7973658.  
  15. ^ Zmuidzinas A, Mamon HJ, Roberts TM, Smith KA (1991). "Interleukin-2-triggered Raf-1 expression, phosphorylation, and associated kinase activity increase through G1 and S in CD3-stimulated primary human T cells". Mol. Cell. Biol. 11 (5): 2794–803. PMID 1708096.  
  16. ^ Moon JJ, Rubio ED, Martino A, Krumm A, Nelson BH (2004). "A permissive role for phosphatidylinositol 3-kinase in the Stat5-mediated expression of cyclin D2 by the interleukin-2 receptor". J. Biol. Chem. 279 (7): 5520–7. doi:10.1074/jbc.M308998200. PMID 14660677.  
  17. ^ a b Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, Hoffmeyer A, van Deursen J, Sangster MY, Bunting KD, Grosveld GC, Ihle JN (1999). "Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells". Immunity 10 (2): 249–59. doi:10.1016/S1074-7613(00)80025-4. PMID 10072077.  
  18. ^ Cantrell DA, Smith KA (1984). "The interleukin-2 T-cell system: a new cell growth model". Science 224 (4655): 1312–6. doi:10.1126/science.6427923. PMID 6427923.  
  19. ^ Smith KA (1989). "The interleukin 2 receptor". Annu. Rev. Cell Biol. 5: 397–425. doi:10.1146/annurev.cb.05.110189.002145. PMID 2688708.  
  20. ^ Smith KA (2006). "The quantal theory of immunity". Cell Res. 16 (1): 11–9. doi:10.1038/ PMID 16467871.  
  21. ^ Turner JM (1993). "IL-2-dependent induction of G1 cyclins in primary T cells is not blocked by rapamycin or cyclosporin A". Int. Immunol. 5 (10): 1199–209. doi:10.1093/intimm/5.10.1199. PMID 8268127.  
  22. ^ Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massague J, Crabtree GR, Roberts JM (1994). "Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin". Nature 372 (6506): 570–3. doi:10.1038/372570a0. PMID 7990932.  
  23. ^ Martino A, Holmes JH, Lord JD, Moon JJ, Nelson BH (2001). "Stat5 and Sp1 regulate transcription of the cyclin D2 gene in response to IL-2". J. Immunol. 166 (3): 1723–9. PMID 11160217.  

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