IL10RB

IL-10RB (also called CRF2-4 or IL-10R2) is a shared class II cytokine receptor subunit that serves as an obligate accessory chain for at least four distinct receptor complexes — those for IL-10, IL-22, IL-26, and IFN-λ — thereby coupling diverse anti-inflammatory and antiviral cytokine signals to JAK-STAT activation (PMID:9463407, PMID:15123776, PMID:30247785). IL-10RB is recruited to pre-formed ligand/R1-chain binary complexes through a conserved ectodomain epitope; conformational changes induced in the ligand by the R1 chain create the IL-10RB binding site, enforcing a sequential assembly mechanism (PMID:15120653, PMID:16982608, PMID:20462497). Intracellularly, IL-10RB-associated Tyk2 controls the amplitude of STAT3 phosphorylation and SOCS3 induction, which mediate anti-inflammatory suppression of TNF-α and other pro-inflammatory cytokines; loss-of-function mutations in IL10RB abolish IL-10 signaling and cause very-early-onset inflammatory bowel disease (PMID:29016674, PMID:33804706, PMID:9463407). The extracellular domain of IL-10RB can be proteolytically shed by KLK2, reducing surface expression and attenuating IL-10-mediated anti-inflammatory signaling (PMID:39106042).

1. 1998 High

   Whether CRF2-4 was functionally required for IL-10 signaling in vivo was unknown; targeted gene disruption showed that CRF2-4-null mice lost IL-10 responsiveness and developed chronic colitis, establishing IL-10RB as an essential IL-10 receptor subunit.

   Evidence Homologous recombination knockout mouse with cytokine responsiveness assays

   PMID:9463407

   Open questions at the time

   • No biochemical mechanism for how IL-10RB contributes to signal transduction was defined
   • Whether IL-10RB participates in other cytokine receptor complexes was unknown
2. 2000 High

   It was unclear whether IL-10RB served additional cytokine systems; reconstitution of IL-22 signaling showed that both IL-22R1 and IL-10RB are required for functional IL-22 receptor assembly and STAT activation, establishing IL-10RB as a shared receptor subunit.

   Evidence Heterologous expression in COS and hamster cells, radiolabeled ligand cross-linking, STAT activation assays, and expression cloning

   PMID:10875937 PMID:11035029

   Open questions at the time

   • The full repertoire of cytokines using IL-10RB was not yet defined
   • Whether IL-10RB binds ligand directly or only in complex was unresolved
3. 2004 High

   The breadth of IL-10RB usage and the mechanism of its recruitment were open questions; neutralizing antibody blockade confirmed that IL-10RB is shared among IL-10, IL-22, IL-26, and IFN-λ complexes, while binding studies demonstrated that IL-10RB engages the IL-22/IL-22R1 binary complex sequentially rather than binding free ligand.

   Evidence Neutralizing antibody blockade, SPR, site-directed mutagenesis, ELISA-based sequential binding assays

   PMID:15120653 PMID:15123776 PMID:15327950

   Open questions at the time

   • Whether sequential assembly also applied to the IL-10 system was not shown
   • Structural basis of the conserved IL-10RB binding epitope remained undetermined
4. 2006 High

   Whether R1-chain-induced conformational changes regulated IL-10RB recruitment was untested for the IL-10 system; SPR and crystal structure comparison showed that IL-10R1 binding reshapes helix A of IL-10 to create the IL-10RB binding site, confirming ordered sequential assembly across cytokine systems.

   Evidence Surface plasmon resonance, crystal structure comparison of free vs. IL-10R1-bound IL-10, cell-based assays

   PMID:16982608

   Open questions at the time

   • No ternary complex crystal structure was available
   • The contribution of IL-10RB intracellular domain to signaling was unknown
5. 2008 High

   The precise IL-10RB contact residues on ligand surfaces needed mapping; comprehensive alanine scanning of IL-22 defined the IL-10RB binding footprint on helices A, D, F and loop AB, delineating it from the IL-22R1 binding site.

   Evidence Alanine scanning mutagenesis, ELISA, cell-based assays

   PMID:18675824

   Open questions at the time

   • Equivalent mapping on IL-10 or IFN-λ was not performed
   • Structural validation by co-crystal was still lacking
6. 2010 High

   No atomic-resolution structure of IL-10RB itself existed; the 2.14 Å crystal structure of the IL-10RB ectodomain, combined with mutagenesis, revealed a conserved binding epitope flanked by flexible clefts that accommodate the structural diversity of its multiple ligand partners.

   Evidence X-ray crystallography at 2.14 Å, alanine scanning mutagenesis, computational ternary complex modeling

   PMID:20462497

   Open questions at the time

   • Experimental ternary complex structures were still modeled computationally
   • Mechanism of intracellular signal initiation upon IL-10RB engagement remained unclear
7. 2017 High

   The signaling contribution of IL-10RB's intracellular domain and its associated kinase Tyk2 were undefined; studies with IL-10R2−/− and Tyk2−/− bone marrow cells showed that IL-10RB influences IL-10R1 conformation and that Tyk2 controls STAT3 phosphorylation amplitude and SOCS3 induction, though Tyk2 is dispensable for some IL-10 responses.

   Evidence Bone marrow-derived macrophages from IL-10R2−/− and Tyk2−/− mice, STAT3 phosphorylation and TNF-α suppression assays

   PMID:29016674

   Open questions at the time

   • Tyk2-independent signaling mechanisms downstream of IL-10RB were not identified
   • Role of IL-10RB intracellular domain beyond Tyk2 association was unresolved
8. 2018 Medium

   Whether IL-10RB participated in antiviral IFN-λ signaling in primary cells was functionally unconfirmed; antibody blockade of IFN-λR1/IL-10RB impaired IFN-λ4-mediated STAT1 phosphorylation and anti-HIV activity in macrophages, confirming IL-10RB as essential for IFN-λ antiviral signaling.

   Evidence Anti-IFN-λR1/IL-10RB antibody blockade, STAT1 phosphorylation, HIV infection assays in macrophages

   PMID:30247785

   Open questions at the time

   • Only IFN-λ4 was tested; generalization to other IFN-λ subtypes was not shown
   • Single laboratory finding
9. 2021 High

   Whether IL-10RB loss-of-function mutations directly cause the VEO-IBD phenotype through defective STAT3/SOCS3 signaling was not demonstrated at the human cellular level; patient iPSC-derived macrophages lacking IL-10RB showed abolished IL-10-STAT3-SOCS3 signaling, which was fully restored by lentiviral or CRISPR-mediated genetic correction.

   Evidence iPSC-derived macrophages from VEO-IBD patients, lentiviral and CRISPR safe-harbor correction, STAT3 phosphorylation and SOCS3 expression assays

   PMID:33804706

   Open questions at the time

   • In vivo gene therapy rescue of IBD has not been demonstrated
   • Contribution of IL-22 and IFN-λ signaling loss to the disease phenotype was not dissected
10. 2024 Medium

    Whether IL-10RB surface expression is regulated post-translationally was unknown; identification of KLK2-mediated cleavage of the IL-10RB extracellular domain (residues 58–63) demonstrated a proteolytic mechanism that reduces surface IL-10RB and attenuates IL-10 anti-inflammatory signaling.

    Evidence Fluorescent peptide substrate assays, flow cytometry, LPS/IFN-γ macrophage functional assays

    PMID:39106042

    Open questions at the time

    • In vivo relevance of KLK2 shedding has not been established
    • Whether shedding affects IL-22 or IFN-λ signaling was not tested
    • Whether other proteases also cleave IL-10RB is unknown

• Key unresolved questions include the experimental structure of a complete ternary signaling complex (ligand/R1/IL-10RB), the Tyk2-independent intracellular signaling pathways mediated by IL-10RB, and the physiological relevance of IL-10RB ectodomain shedding in disease settings.
• No experimental ternary complex structure exists
• Tyk2-independent signaling downstream of IL-10RB is uncharacterized
• In vivo consequences of IL-10RB shedding are unknown