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Introduction

Interleukin 33 is a cytokine member of the IL-1 superfamily. Cytokines are proteins involved in cell signaling. Their role is to regulate the function and the activity of other cells. IL-33 is involved in innate and adaptive immune responses.

In 2005, IL-33 was identified as a ligand for the transmembrane receptor ST2 and it IL-1 receptor accessory protein (IL-1RAcP), both members of the interleukin-1 receptor family. IL-33/ST2 signaling is involved in T-cell immune responses.

We will focuse on the interaction bewteen IL33 and the ST2 ectodomain (as you can see ).

Function

Caracteristics of IL-33:

IL-33 is consitutively expressed in several cells, such as epithelial or endothelial cells. IL-33 is also expressed in an inducible way by immune cells. In this case, the consitutive expression of IL-33 is very low or absent.

Target cells:

ST2 exists in a soluble form (sST2) and a transmembrane form (ST2L). We will focuse on the transmembrane form, which interacts with IL33. ST2L are expressed in T lymphocytes, when they are specialising into Th2 cells (T helper type 2 cells, a specific type of T lymphocytes). This specialisation occurs in the presence of IL4, expeted to be secreted by polynuclear basophils.

IL-33 is an extracellular cytokine involved in the polarization of Th2 cells and activation of other immune cells, such as basophils and eosinophils.

expliquer type 2 immune response

Recently, it has been discovered that type 2 innate lymphoid cells (ILC2s) are major targets of IL-33. Indeed, when ILC2s is stimulated by IL-33, ILC2s show high levels of ST2 and release high quantities of Th2 cytokines. It initiates type 2 immune responses during allergic diseases or against helminth infection.

Structure

Understanding:

The understanding of the interaction of IL-33 with its receptors has been discovered thanks to the determination of the crystal structure of IL-33 in complex with ectodomain of ST2 as shown here.

Besides, the combination of crystallography and small-angle X-ray-scattering methods reveal that ST2 has a very flexible conformation allowed by the flexibility between the D3 and D1D2 module (domains of ST2), contrary to IL-1RAcP.

This conformational specificity provides a structural view of ligand-binding with IL-1 primary receptors. Moreover, the rigidity of IL-1RAcP explains that it can not bind ligand directly.

Overall structure:

In humans, IL-33 in its full length is composed of 270 residues and is biologically active. The model includes IL-33 residues Ser117 to Asn171, Gly179 to Val252, and Glu261 to Ser268 and ST2 residues Ser21 to Ser51, Ser56 to Lys223, Asn232 to Gly271, and Gly279 to Arg317.

The structure of IL-33 consists in a 12-stranded β-trefoil loops with changing conformations. Specific loops, such as the β4-β5 loop, are involved in the interaction with the accessory receptor IL-1RAcP when IL-33 is bind to ST2.

ST2 is constituted of three IgG-like domains (D1 to D3) as highlighted here. D1 and D2 gather to form a single D1D2 module, connected through a linker with the D3 domain.

IL-33/ST2 interactions:

In the complex, IL-33 interacts with the three domains of ST2. The binding interface is very large and composed of two separate sites.

In the first binding site, thirteen IL-33 residues from β-loops are in contact with the D1D2 module of ST2: Glu144, Glu148, Asp149, and Asp244 form a bridge with ST2 residues Arg38, Lys22, Arg198, and Arg35, respectively. Besides, Glu144 and Asp149 form hydrogen bonds with main-chain atoms of ST2.

In the second binding site, eight IL-33 residues from β-strands interact with the D3 domain of ST2.

There are both hydrophobic and hydrophilic interactions. Residues of IL-33 form an hydrophobic cluster (Tyr164 and Leu182 and ST2 residues Leu246, Leu306, and Leu311). A salt-bridge interaction occurs between acidic residue Glu165 and Arg313 of ST2.