Survey
The Class II cytokine receptor (CRF2) family: overview and patterns of receptor–ligand interactions

https://doi.org/10.1016/j.cytogfr.2003.10.001Get rights and content

Abstract

Expanded genomic information has driven the discovery of new members of the human Class II family of cytokine receptors (CRF2), which now includes 12 proteins. The corresponding cytokines have been identified, paired with their receptors and initially characterized for function. These cytokines include: a new human Type I IFN, IFN-κ; molecules related to IL-10 (IL-19, IL-20, IL-22, IL-24, IL-26); and IFN-λs (IL-28/29), which have antiviral and cell stimulatory activities reminiscent of Type I IFNs, but act through a distinct receptor. In response to ligand binding, the CRF2 proteins form heterodimers, leading to cytokine-specific cellular responses; these diverse physiological functions are just beginning to be explored. Progress in structural and mutational analysis of ligand–receptor interactions now presents a more reliable framework for understanding receptor–ligand interactions, and for predicting key regions in less well studied members of the CRF2 family. The relationships between the CRF2 proteins will be summarized, as will the progress in identifying patterns of receptor interactions with ligands.

Introduction

The cytokine receptors form a structural family that can be divided into two classes based on conserved features in the extracellular domains (ECDs), particularly the number and spacing of cysteine and proline residues [1], [2]. This classification promoted investigations into the evolution, structure and function of the cytokine receptors, and has permitted useful generalizations about the members of the families, and judicious extrapolations from one cytokine/receptor pair to another.

Until recently, the Class II cytokine receptor family (CRF2; also denoted HCRII, for helical cytokine receptor, Class II) included both subunits of the Type I interferon receptor (IFNAR-1 and IFNAR-2) and of the Type II IFN receptor (IFNGR-1 and IFNGR-2), tissue factor (TF), the ligand-binding chain of the IL-10 receptor (IL-10R1), and an “orphan” receptor, CRF2–4, later found to be the second subunit of the IL-10 receptor (IL-10R2). Improved genomic databases, sequence searching algorithms and investigator persistence in the face of low sequence homology permitted the discovery of five new members of the Class II cytokine receptor family (CRF2) in humans.

Parallel to the work on the receptors, new cytokines have been discovered by bioinformatic approaches, and by functional assays. Expression and co-expression of various CRF2 members and testing with putative ligands has permitted the pairing of ligands with receptors. However, an understanding of the biological/physiological roles and therapeutic potential of these ligands is still in its infancy.

The CRF2 receptors are listed in Table 1A and B. The corresponding Class II cytokines are organized by families in Table 2, and are diagrammatically paired with their receptors in Fig. 1. All the receptors except TF appear to function as heterodimers (see below).

Although this review will focus on the CRF2 family of receptors, it is worthwhile to introduce their ligands, which can be divided into several groups based on both structure and function (Table 2).

  • (1)

    The Type I IFNs [3], including the most recent human additions, IFN-κ [4] and IFN-ϵ [102] (also, IFN-τ in ruminants [5], and, in mice, limitin [6], [7], [8], [9]) were defined by their potent antiviral activity. However, even the IFN-αs and IFN-β stimulate an increasing list of activities which link innate and acquired immunity, including dendritic cell maturation, T-helper cell biasing, B cell differentiation, and NK activation [10]. The Type I IFNs all signal through IFNAR-1 and IFNAR-2, but their in vitro, physiological roles and therapeutic applications suggest that at least some of them are not biologically equivalent and interchangeable. While the functional repertoire of the “classical” Type I IFNs continues to expand, the functions of the newer members are only beginning to be explored.

  • (2)

    Type II IFN consists solely of IFN-γ [11], [12], [13]. Despite its classification as an interferon with antiviral activity, the genetic and physiological data point to a stronger role in protection against intracellular organisms and parasites such as mycobacteria and Listeria. IFN-γ affects diverse aspects of innate immunity, such as the activation of macrophages, and has strong effects on acquired responses, particularly in cell-mediated immunity, where it promotes the development of CD4+ Th1 cells and cytotoxic CD8+ T cells, while suppressing CD4+ Th2 cells. Studies with murine model tumor systems also demonstrate a role for IFN-γ (and T lymphocytes) in the natural suppression of tumor development [13]. IFN-γ utilizes the receptor subunits IFNGR-1 and IFNGR-2.

  • (3)

    A recently expanded group consists of IL-10 and its relatives, IL-19, IL-20, IL-22, IL-24 and IL-26 [14], [15], [16], [17]. These proteins are distantly related to one another (20–25% sequence identity), and have quite diverse functions, only some of which are currently known. They signal through different combinations of CRF2 proteins, with some sharing of receptor subunits (Table 1; Fig. 1). Viral homologues of IL-10, which serve as important virulence factors, have been found in large DNA viruses such as Epstein-Barr virus, cytomegalovirus and poxviruses [16], [17].

  • (4)

    The new IFN-λ or IL-28/29 family is comprised of three closely related proteins found together in the human genome [18], [19]. While these proteins have little sequence similarity to Type I IFNs, they share with Type I IFNs their antiviral activity, inducibility by viruses, and induction of at least several IFN-inducible proteins (MxA, 2′–5′ oligoadenylate synthetase, PKR), stimulation of transcription factors (ISGF-3) and intracellular kinases (Tyk2, Jak1). However, they utilize the receptor protein pair CRF2–12 (a.k.a. IFN-λR1 or IL-28Rα) and CRF2–4 (IL-10R2). A major question is whether the IFN-λs primarily play a back-up role to the Type I IFNs, or whether they have one or more undiscovered unique functions (see below).

  • (5)

    Finally, Factor VIIa, the ligand for tissue factor (TF) is truly an outlier, being dissimilar from the other CRF2-related cytokines in both structure and function [20]. It will not be further discussed in this review.

Several structure/function reviews have appeared for the best studied cytokine receptors, particularly those with crystal structures [21], [22]. In addition, the genetics, evolution and structure of the chromosome 21-encoded CRF2 receptors, particularly IFNAR, have been summarized [23].

This review will update and expand these, with the inclusion of the newly discovered CRF2 family members. After presenting an overview of the receptor family, we will focus on recent structure and function studies of ligand binding, demonstrating the pattern of receptor interactions that has emerged. These observations combined with homology modeling of these structurally conserved proteins provide a strong starting point for future structure/function studies of ligand binding and for an understanding of ligand specificity by the CRF2 receptors.

Section snippets

The Class II cytokine receptors (CRF2)

The CRF2 proteins are tripartite single-pass transmembrane proteins defined by structural similarities in the extracellular domain, which includes the ligand-binding residues [1], [2], [24]. The 200-amino-acid extracellular domain, more specifically denoted a cytokine receptor homology (CRH) domain, is composed of 2 tandem fibronectin Type III (FNIII) domains, a structural motif in the immunoglobulin fold superfamily (Fig. 2). We will refer to the amino-terminal FNIII domain, distal to the

Into the future

Structural (crystallographic or NMR) data or structure/function mutagenesis data on ligand–receptor complexes are only available for 4 of 12 CRF2 proteins. Nevertheless, mapping the receptor contact residues from crystal structures and from mutagenesis results onto the sequence alignments provides a fairly consistent picture of the use of various parts of the receptors in ligand binding (Fig. 3, Fig. 5).

As with several Class I receptors, many of the ligand binding interactions are dominated by

Acknowledgements

This study was supported in part by United States Public Health Services Grant RO1 AI51139 from the National Institute of Allergy and Infectious Diseases and by American Heart Association Grant AHA #0245131N to S.V.K.

References (102)

  • S.V Kotenko et al.

    Other kinases can substitute for Jak2 in signal transduction by interferon-gamma

    J. Biol. Chem.

    (1996)
  • G Muthukumaran et al.

    Chimeric erythropoietin-interferon gamma receptors reveal differences in functional architecture of intracellular domains for signal transduction

    J. Biol. Chem.

    (1997)
  • D Novick et al.

    Soluble interferon-alpha receptor molecules are present in body fluids

    FEBS Lett.

    (1992)
  • C.M Owczarek et al.

    Cloning and characterization of soluble and transmembrane isoforms of a novel component of the murine Type I interferon receptor, IFNAR 2

    J. Biol. Chem.

    (1997)
  • M.P Hardy et al.

    The soluble murine Type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties

    Blood

    (2001)
  • J.R Cook et al.

    Differential responsiveness of a splice variant of the human Type I interferon receptor to interferons

    J. Biol. Chem.

    (1996)
  • J.J O’Shea et al.

    Cytokine signaling in 2002: new surprises in the Jak/Stat pathway

    Cell

    (2002)
  • C.D Krause et al.

    Seeing the light: preassembly and ligand-induced changes of the interferon gamma receptor complex in cells

    Mol. Cell Proteomics

    (2002)
  • R Sadir et al.

    Caveolae and clathrin-coated vesicles: two possible internalization pathways for IFN-gamma and IFN-gamma receptor

    Cytokine

    (2001)
  • D.J Thiel et al.

    Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex

    Struct. Fold Des.

    (2000)
  • K Josephson et al.

    Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site

    Immunity

    (2001)
  • Y.A Muller et al.

    The crystal structure of the extracellular domain of human tissue factor refined to 1.7 Å resolution

    J. Mol. Biol.

    (1996)
  • J.H Chill et al.

    The human Type I interferon receptor: NMR structure reveals the molecular basis of ligand binding

    Structure

    (2003)
  • J Piehler et al.

    Mutational and structural analysis of the binding interface between Type I interferons and their receptor Ifnar2

    J. Mol. Biol.

    (1999)
  • E.C Cutrone et al.

    Identification of critical residues in bovine IFNAR-1 responsible for interferon binding

    J. Biol. Chem.

    (2001)
  • M Randal et al.

    The structure and activity of a monomeric interferon-gamma:alpha-chain receptor signaling complex

    Structure

    (2001)
  • J.A Langer et al.

    Bovine Type I interferon receptor protein BoIFNAR-1 has high-affinity and broad specificity for human Type I interferons

    FEBS Lett.

    (1998)
  • M Lewerenz et al.

    Shared receptor components but distinct complexes for alpha and beta interferons

    J. Mol. Biol.

    (1998)
  • Y Mitsui et al.

    Structural, functional and evolutionary implications of the three-dimensional crystal structure of murine interferon-β

    Pharmacol. Ther.

    (1993)
  • G Uzé et al.

    Domains of interaction between alpha interferon and its receptor components

    J. Mol. Biol.

    (1994)
  • J Piehler et al.

    New structural and functional aspects of the Type I interferon–receptor interaction revealed by comprehensive mutational analysis of the binding interface

    J. Biol. Chem.

    (2000)
  • G.P Vigers et al.

    X-ray crystal structure of a small antagonist peptide bound to interleukin-1 receptor type 1

    J. Biol. Chem.

    (2000)
  • E.C Cutrone et al.

    Contributions of cloned Type I interferon receptor subunits to differential ligand binding

    FEBS Lett.

    (1997)
  • M Aguet et al.

    Molecular cloning and expression of the human interferon-gamma receptor

    Cell

    (1988)
  • J Soh et al.

    Identification and sequence of an accessory factor required for activation of the human interferon gamma receptor

    Cell

    (1994)
  • S Hemmi et al.

    A novel member of the interferon receptor family complements functionality of the murine interferon gamma receptor in human cells

    Cell

    (1994)
  • G Uzé et al.

    Genetic transfer of a functional human interferon-α receptor into a mouse cells: cloning and expression of its cDNA

    Cell

    (1990)
  • D Novick et al.

    The human interferon alpha/beta receptor: characterization and molecular cloning

    Cell

    (1994)
  • P Domanski et al.

    Cloning and expression of a long form of the beta subunit of the interferon alpha beta receptor that is required for signaling

    J. Biol. Chem.

    (1995)
  • M.H Xie et al.

    Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2–4 and IL-22R

    J. Biol. Chem.

    (2000)
  • S.V Kotenko et al.

    Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes

    J. Biol. Chem.

    (2001)
  • H Blumberg et al.

    Interleukin 20: discovery, receptor identification, and role in epidermal function

    Cell

    (2001)
  • M Wang et al.

    Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2

    J. Biol. Chem.

    (2002)
  • R.M Roberts et al.

    The evolution of the Type I interferons

    J. Interferon Cytokine Res.

    (1998)
  • K Oritani et al.

    An interferon-like cytokine that preferentially influences B-lymphocyte precursors

    Nat. Med.

    (2000)
  • I Takahashi et al.

    A new IFN-like cytokine, limitin, modulates the immune response without influencing thymocyte development

    J. Immunol.

    (2001)
  • K Oritani et al.

    Limitin: an interferon-like cytokine without myeloerythroid suppressive properties

    J. Mol. Med.

    (2001)
  • E.A Bach et al.

    The IFN gamma receptor: a paradigm for cytokine receptor signaling

    Annu. Rev. Immunol.

    (1997)
  • S Pestka

    The interferon receptors

    Semin. Oncol.

    (1997)
  • K.W Moore et al.

    Interleukin-10 and the interleukin-10 receptor

    Annu. Rev. Immunol.

    (2001)
  • Cited by (170)

    • Bioconjugation strategies and clinical implications of Interferon-bioconjugates

      2022, European Journal of Pharmaceutics and Biopharmaceutics
    • Cytokine Receptors and Their Ligands

      2022, Encyclopedia of Cell Biology: Volume 1-6, Second Edition
    • Cytokine Therapy

      2022, Encyclopedia of Infection and Immunity
    View all citing articles on Scopus
    1

    Present Address: DarPharma, Inc., 215 Cloister Court, Chapel Hill, NC 27514, USA. Tel.: +1-919-403-4348; fax: +1-919-403-4369.

    2

    Tel: +1-973-972-3134; fax: +1-973-972-5594.

    View full text