IL-2 receptor

The interleukin-2 receptor (IL-2R) is 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-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.

Additional recommended knowledge

Better weighing performance in 6 easy steps

Daily Visual Balance Check

How to quickly check pipettes?

Discovery and characterization

The IL-2 receptor (IL-2R) was the first interleukin receptor to be described and characterized.^[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 = 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.^[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 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.^[9] 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.^[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 comprised of 4 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.

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 (or IL-15 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. 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.^[24]

References