IL-12 Family Receptor Review

IL-12 family receptor chains are used by multiple IL-12 family cytokines. IL-12 signals via IL-12Rβ1 and IL-12Rβ2, whereas IL-23 signals via IL-12Rβ1 and IL-23R. On the contrary, IL-27 uses gp130 and IL-27R (WSX-1). whereas IL-35 signals via gp130 and IL-12Rβ2. IL-35 is unusual in that it can also signal via two additional receptor-chain compositions: gp130-gp130 and IL-12Rβ2–lL-12Rβ2 homodimers.

Below will briefly discuss structures and functions of IL-12 family receptors, including IL-12 receptor, IL-23 receptor, IL-27 receptor, and IL-35 receptor.

IL-12 family ligand and congnate receptor

IL-12 Receptor

The IL-12 receptor (IL-12R) is composed of two subunits, IL-12Rβ1 and IL-12Rβ2. They activate the Janus kinase (JAK)–STAT (signal transducer and activator of transcription) pathway of signal transduction. IL-12Rβ1 and IL-12Rβ2, have extensive homology to gp130, the common receptor β-chain of the IL-6-like cytokine superfamily. They are type I transmembrane glycoproteins, with molecular weights of ~100 kDa (IL-12Rβ1) and ~130 kDa (IL-12Rβ2). Co-expression of IL-12Rβ1 and IL-12Rβ2 is required for the generation of highaffinity (50 pM) IL-12-binding sites, and the IL-12Rβ2 subunit functions as the signal transducing component of the high-affinity receptor complex.

IL-12R is expressed mainly by activated T cells and NK cells. Expression of IL-12R has been shown also on other cell types, such as DCs and B-cell lines. IL-12R is undetectable on most resting T cells, but it is expressed at a low level by NK cells, which probably explains the ability of these cells, and possibly of certain subsets of T cell, to respond rapidly to IL-12. Activation of T cells through the TCR upregulates the transcription and expression of both chains of IL-12R, and this upregulation - in particular that of the β2-chain - is enhanced by IL-12 itself, IFN-α, IFN-γ, tumour-necrosis factor (TNF) and co-stimulation through CD28.

IL-23 Receptor

Recently, it was found that interleukin-12 (IL-12) p40 associates not only with IL-12 p35, but also with another molecule, p19, to form a new heterodimeric cytokine known as IL-23. IL-23 binds to a receptor that is formed by IL-12Rβ1 and a new second chain, IL-23R.

The IL-23 receptor (IL-23R) contains all intracellular signaling domains and an Ig domain, but is lacking the 3 membrane-proximal FNIII domains and instead contains a long peptide that connects it to the transmembrane region, similar to IL-6Rα.

The high affinity IL-23 receptor derives from the combination of IL-12Rβ1 with a unique IL-23 receptor subunit (IL-23R) and biologic effects of IL-23 on its target cells are mediated through activation of TYK2, JAK2, STAT3 and STAT4.

Many innate immune cells including DCs, macrophages, B cells and endothelial cells produce IL-23 and the high affinity IL-23 receptor is expressed on activated T cells and immune cells including Th17 cells, cd T cells, natural killer T (NKT) cells and innate lymphoid cells (ILCs).

IL-23 receptor expression on cd T cells is implicated in immunopathogenic mechanisms of experimental autoimmune uveoretinitis (EAU) and it has been suggested that IL-23 plays an important role in birdshot retinochoroidopathy.

IL-27 Receptor

IL-27 binds to a heterodimeric receptor complex, which is composed of a ligand-binding chain, IL-27RA (WSX-1, TCCR), and an additional signal-transducing chain, gp130. The former belongs to the class I cytokine receptor family (TCCR). B (activated) cells, DCs, Endothelial (activated) cells, mast cells, monocytes, naїve T cells, and NK cells are all recognized as the IL-27R producer cells.

IL-27RA contains five tandem FNIII domains similar to gp130 and IL-12Rβ2, however they lack the N-terminal Ig-like domain, as well as some of the tyrosine motifs in the intracellular domains. IL-27RA includes a cytoplasmatic domain with Box 1 motif binding sites for JAK1/2, which contributes to signal transduction of the IL-27RA/gp130 dimer. The common gp130 chain is shared by several other receptors for signaling of cytokines, such as IL-6, IL-11, and leukemia inhibitory factor. The situation becomes even more complex with heterodimers
of CLF-1/p28 binding to a trimeric receptor complex composed of IL-27RA/gp130/IL-6RA.

IL-35 Receptor

Signaling of each IL-12 family member utilizes a unique receptor. The receptor for IL-35 is unique in sharing the gp130 subunit with the IL-27 receptor and the IL-12Rβ2 subunit with the IL-12 receptor.

Unlike other members of IL-12 family, IL-35 encompasses four receptors including IL-12R-β2-IL-27R (WSX-1), IL-12R-β2-IL-12R-β2, IL-12R-β2-gp130, and gp130-gp130.

IL-35 can signal through homodimers of gp130 and IL-12Rβ2. Expression of IL-12Rβ2 has also been shown on cell types other than Treg cells, including B cells and dendritic cells, which may affect the spectrum of IL-35 bioactivity in the immune system. IL-12Rβ2 is mainly induced by IFN-α and IFN-γ on human T and natural killer cells but not expressed by naïve resting T cells. IL-12Rβ2 expression promotes development through a Th1 pathway.

gp130 is ubiquitously expressed in almost all organs. The signaling pathway of IL-35 accomplished through a heterodimer of IL-12Rβ2–gp130 or a homodimer of IL-12Rβ2–IL-12Rβ2 or gp130-gp130 could affect the suppressive activity of IL-35.

References

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3. Choi, J., Leung, P. S., Bowlus, C., & Gershwin, M. E. (2015). IL-35 and autoimmunity: a comprehensive perspective. Clinical reviews in allergy & immunology, 49(3), 327-332.
4. Sun, L., He, C., Nair, L., Yeung, J., & Egwuagu, C. E. (2015). Interleukin 12 (IL-12) family cytokines: role in immune pathogenesis and treatment of CNS autoimmune disease. Cytokine, 75(2), 249-255.
5. Vignali, D. A., & Kuchroo, V. K. (2012). IL-12 family cytokines: immunological playmakers. Nature immunology, 13(8), 722.