|interleukin 2 receptor, alpha|
|Alt. symbols||IL2R CD25|
|Locus||Chr. 10 p15.1|
|interleukin 2 receptor, beta|
|Locus||Chr. 22 q13|
|interleukin 2 receptor, gamma (severe combined immunodeficiency)|
|Alt. symbols||SCIDX1, IMD4, CD132|
|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 IL-2. The IL-2R is made up of 3 subunits - alpha (α), beta (β) and gamma (γ) - non-covalently associating. 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. 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), beta (β) and gamma (γ) 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.
Structure-activity relationships of the IL-2/IL-2R interaction
||This article may be confusing or unclear to readers. (April 2012)|
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. 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.
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 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.
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. Given that the half-time for internalization of IL-2 occupied IL-2Rs is ~ 15 minutes, 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. 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. 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. As well, via the activation of the PI3K pathway, an inhibitor of cyclin-D/CDK activity (p27) is targeted for degradation. Both of these biochemical events, as well as others activated via the IL-2R 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 IL-2R also signals negative feedback loops that function to inhibit IL-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 (T regulatory cells) 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.
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