Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells

Glassman, Caleb R.; Mathiharan, Yamuna Kalyani; Jude, Kevin M.; Su, Leon; Panova, Ouliana; Lupardus, Patrick J.; Spangler, Jamie B.; Ely, Lauren K.; Thomas, Christoph; Skiniotis, Georgios; Garcia, K. Christopher

doi:10.1016/j.cell.2021.01.018

Title: Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells

Journal Article · Thu Feb 18 00:00:00 EST 2021 · Cell

DOI:https://doi.org/10.1016/j.cell.2021.01.018· OSTI ID:1781662

^[1];

^[1]; Panova, Ouliana ^[1];

^[1];

^[1]; Skiniotis, Georgios ^[1]; Garcia, K. Christopher ^[1]

Stanford Univ., CA (United States). School of Medicine

Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a receptor signaling subunit. In this paper, we present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor (IL-23R) complexes, which reveal “non-canonical” topologies where IL-12Rβ1 directly engages the common p40 subunit. We targeted the shared IL-12Rβ1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFNγ) induction by CD8+ T cells but impaired cytokine production from natural killer (NK) cells in vitro. These cell-biased properties were recapitulated in vivo, where IL-12 partial agonists elicited anti-tumor immunity to MC-38 murine adenocarcinoma absent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structural mechanism of receptor sharing used by IL-12 family cytokines provides a protein interface blueprint for tuning this cytokine axis for therapeutics.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); Mathers Foundation; Ludwig Foundation; National Science Foundation (NSF); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institute of General Medical Sciences (NIGMS)

Grant/Contract Number:: AC02-76SF00515; R01-AI51321; DGE-1656518; AC02-05CH11231

OSTI ID:: 1781662

Journal Information:: Cell, Vol. 184, Issue 4; ISSN 0092-8674

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (81)

Activation of natural killer cells with interleukin 2 (IL-2) and IL-12 increases perforin binding and subsequent lysis of tumour cells: Activation With IL-2 and IL-12 Increases Perforin Binding Lehmann, Christof; Zeis, Matthias; Uharek, Lutz British Journal of Haematology, Vol. 114, Issue 3 https://doi.org/10.1046/j.1365-2141.2001.02995.x	journal	September 2001
Preactivation with IL-12, IL-15, and IL-18 Induces CD25 and a Functional High-Affinity IL-2 Receptor on Human Cytokine-Induced Memory-like Natural Killer Cells Leong, Jeffrey W.; Chase, Julie M.; Romee, Rizwan Biology of Blood and Marrow Transplantation, Vol. 20, Issue 4 https://doi.org/10.1016/j.bbmt.2014.01.006	journal	April 2014
The interleukin-12 subunit p40 specifically inhibits effects of the interleukin-12 heterodimer Mattner, Frank; Fischer, Susanne; Guckes, Stefanie European Journal of Immunology, Vol. 23, Issue 9 https://doi.org/10.1002/eji.1830230923	journal	September 1993
IL-12 family cytokines: immunological playmakers Vignali, Dario A. A.; Kuchroo, Vijay K. Nature Immunology, Vol. 13, Issue 8 https://doi.org/10.1038/ni.2366	journal	July 2012
A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions Wojtowicz, Woj M.; Vielmetter, Jost; Fernandes, Ricardo A. Cell, Vol. 182, Issue 4 https://doi.org/10.1016/j.cell.2020.07.025	journal	August 2020
Revisiting Interleukin-12 as a Cancer Immunotherapy Agent Berraondo, Pedro; Etxeberria, Iñaki; Ponz-Sarvise, Mariano Clinical Cancer Research, Vol. 24, Issue 12 https://doi.org/10.1158/1078-0432.CCR-18-0381	journal	March 2018
Th17 and Regulatory T Cells in Mediating and Restraining Inflammation Littman, Dan R.; Rudensky, Alexander Y. Cell, Vol. 140, Issue 6 https://doi.org/10.1016/j.cell.2010.02.021	journal	March 2010
Structure and function in rhodopsin: High-level expression of rhodopsin with restricted and homogeneous N-glycosylation by a tetracycline-inducible N-acetylglucosaminyltransferase I-negative HEK293S stable mammalian cell line Reeves, P. J.; Callewaert, N.; Contreras, R. Proceedings of the National Academy of Sciences, Vol. 99, Issue 21 https://doi.org/10.1073/pnas.212519299	journal	October 2002
Molecular Mechanisms of IFN-γ to Up-Regulate MHC Class I Antigen Processing and Presentation Zhou, Fang International Reviews of Immunology, Vol. 28, Issue 3-4 https://doi.org/10.1080/08830180902978120	journal	January 2009
Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8+ T cells Rubinstein, Mark P.; Su, Ee Wern; Suriano, Samantha Cancer Immunology, Immunotherapy, Vol. 64, Issue 5 https://doi.org/10.1007/s00262-015-1655-y	journal	February 2015
T cell receptor antagonist peptides induce positive selection Hogquist, Kristin A.; Jameson, Stephen C.; Heath, William R. Cell, Vol. 76, Issue 1, p. 17-27 https://doi.org/10.1016/0092-8674(94)90169-4	journal	January 1994
Antitumor and antimetastatic activity of interleukin 12 against murine tumors. Brunda, M. J.; Luistro, L.; Warrier, R. R. Journal of Experimental Medicine, Vol. 178, Issue 4 https://doi.org/10.1084/jem.178.4.1223	journal	October 1993
Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12 Yoon, Christina; Johnston, Steven C.; Tang, Jin The EMBO Journal, Vol. 19, Issue 14 https://doi.org/10.1093/emboj/19.14.3530	journal	July 2000
Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1 Bloch, Yehudi; Bouchareychas, Laura; Merceron, Romain Immunity, Vol. 48, Issue 1 https://doi.org/10.1016/j.immuni.2017.12.008	journal	January 2018
Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response Tseng, D.; Volkmer, J. -P.; Willingham, S. B. Proceedings of the National Academy of Sciences, Vol. 110, Issue 27 https://doi.org/10.1073/pnas.1305569110	journal	May 2013
Structural Biology of Shared Cytokine Receptors Wang, Xinquan; Lupardus, Patrick; LaPorte, Sherry L. Annual Review of Immunology, Vol. 27, Issue 1 https://doi.org/10.1146/annurev.immunol.24.021605.090616	journal	April 2009
Isolating and engineering human antibodies using yeast surface display Chao, Ginger; Lau, Wai L.; Hackel, Benjamin J. Nature Protocols, Vol. 1, Issue 2 https://doi.org/10.1038/nprot.2006.94	journal	July 2006
Collaboration gets the most out of software Morin, Andrew; Eisenbraun, Ben; Key, Jason eLife, Vol. 2 https://doi.org/10.7554/eLife.01456	journal	September 2013
Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. Kobayashi, M.; Fitz, L.; Ryan, M. Journal of Experimental Medicine, Vol. 170, Issue 3 https://doi.org/10.1084/jem.170.3.827	journal	September 1989
Cytokine activation induces human memory-like NK cells Romee, Rizwan; Schneider, Stephanie E.; Leong, Jeffrey W. Blood, Vol. 120, Issue 24 https://doi.org/10.1182/blood-2012-04-419283	journal	December 2012
Regulation of the Interleukin (IL)-12R β2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells Szabo, Susanne J.; Dighe, Anand S.; Gubler, Ueli Journal of Experimental Medicine, Vol. 185, Issue 5 https://doi.org/10.1084/jem.185.5.817	journal	March 1997
Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab Benson, Jacqueline M.; Sachs, Clifford W.; Treacy, George Nature Biotechnology, Vol. 29, Issue 7 https://doi.org/10.1038/nbt.1903	journal	July 2011
Novel p19 Protein Engages IL-12p40 to Form a Cytokine, IL-23, with Biological Activities Similar as Well as Distinct from IL-12 Oppmann, Birgit; Lesley, Robin; Blom, Bianca Immunity, Vol. 13, Issue 5 https://doi.org/10.1016/S1074-7613(00)00070-4	journal	November 2000
Structural Basis for the Dual Recognition of IL-12 and IL-23 by Ustekinumab Luo, Jinquan; Wu, Sheng-Jiun; Lacy, Eilyn R. Journal of Molecular Biology, Vol. 402, Issue 5 https://doi.org/10.1016/j.jmb.2010.07.046	journal	October 2010
IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease Dambuza, Ivy M.; He, Chang; Choi, Jin Kyeong Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-00838-4	journal	September 2017
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix Liebschner, Dorothee; Afonine, Pavel V.; Baker, Matthew L. Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 10 https://doi.org/10.1107/S2059798319011471	journal	October 2019
A Receptor for the Heterodimeric Cytokine IL-23 Is Composed of IL-12Rβ1 and a Novel Cytokine Receptor Subunit, IL-23R Parham, Christi; Chirica, Madaline; Timans, Jacqueline The Journal of Immunology, Vol. 168, Issue 11 https://doi.org/10.4049/jimmunol.168.11.5699	journal	June 2002
Direct Interaction of STAT4 with the IL-12 Receptor Yao, Betty Bei; Niu, Ping; Surowy, Carol S. Archives of Biochemistry and Biophysics, Vol. 368, Issue 1 https://doi.org/10.1006/abbi.1999.1302	journal	August 1999
Cooperation of Natural Killer Cell Stimulatory Factor/Interleukin-12 with Other Stimuli in the Induction of Cytokines and Cytotoxic Cell-Associated Molecules in Human T and NK Cells Aste-Amezaga, Miguel; D'Andrea, Annalisa; Kubin, Marek Cellular Immunology, Vol. 156, Issue 2 https://doi.org/10.1006/cimm.1994.1192	journal	July 1994
Structure of an Extracellular gp130 Cytokine Receptor Signaling Complex Chow, D. -c. Science, Vol. 291, Issue 5511 https://doi.org/10.1126/science.1058308	journal	March 2001
Site-Specific Biotinylation of Purified Proteins Using BirA Fairhead, Michael; Howarth, Mark Site-Specific Protein Labeling https://doi.org/10.1007/978-1-4939-2272-7_12	book	December 2014
Treatment of disseminated ovarian cancer using nonviral interleukin-12 gene therapy delivered intraperitoneally Fewell, Jason G.; Matar, Majed M.; Rice, Jennifer S. The Journal of Gene Medicine, Vol. 11, Issue 8 https://doi.org/10.1002/jgm.1356	journal	August 2009
Neutralization of Human Interleukin 23 by Multivalent Nanobodies Explained by the Structure of Cytokine–Nanobody Complex Desmyter, Aline; Spinelli, Silvia; Boutton, Carlo Frontiers in Immunology, Vol. 8 https://doi.org/10.3389/fimmu.2017.00884	journal	August 2017
IL-27, a Heterodimeric Cytokine Composed of EBI3 and p28 Protein, Induces Proliferation of Naive CD4+ T Cells Pflanz, Stefan; Timans, Jackie C.; Cheung, Jeanne Immunity, Vol. 16, Issue 6 https://doi.org/10.1016/S1074-7613(02)00324-2	journal	June 2002
CTFFIND4: Fast and accurate defocus estimation from electron micrographs Rohou, Alexis; Grigorieff, Nikolaus Journal of Structural Biology, Vol. 192, Issue 2 https://doi.org/10.1016/j.jsb.2015.08.008	journal	November 2015
A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice: Molecular immunology Wang, Xiaoqian; Wei, Yinxiang; Xiao, He European Journal of Immunology, Vol. 46, Issue 6 https://doi.org/10.1002/eji.201546095	journal	April 2016
An unusual cytokine:Ig-domain interaction revealed in the crystal structure of leukemia inhibitory factor (LIF) in complex with the LIF receptor Huyton, T.; Zhang, J. -G.; Luo, C. S. Proceedings of the National Academy of Sciences, Vol. 104, Issue 31 https://doi.org/10.1073/pnas.0705577104	journal	July 2007
The JAK-STAT Signaling Pathway: Input and Output Integration Murray, Peter J. The Journal of Immunology, Vol. 178, Issue 5 https://doi.org/10.4049/jimmunol.178.5.2623	journal	February 2007
Intraepithelial Type 1 Innate Lymphoid Cells Are a Unique Subset of IL-12- and IL-15-Responsive IFN-γ-Producing Cells Fuchs, Anja; Vermi, William; Lee, Jacob S. Immunity, Vol. 38, Issue 4 https://doi.org/10.1016/j.immuni.2013.02.010	journal	April 2013
New tools for automated high-resolution cryo-EM structure determination in RELION-3 Zivanov, Jasenko; Nakane, Takanori; Forsberg, Björn O. eLife, Vol. 7 https://doi.org/10.7554/eLife.42166	journal	November 2018
IL-12 and IL-7 synergize to control mucosal-associated invariant T-cell cytotoxic responses to bacterial infection Wallington, Joshua C.; Williams, Anthony P.; Staples, Karl J. Journal of Allergy and Clinical Immunology, Vol. 141, Issue 6 https://doi.org/10.1016/j.jaci.2017.08.009	journal	June 2018
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy Zheng, Shawn Q.; Palovcak, Eugene; Armache, Jean-Paul Nature Methods, Vol. 14, Issue 4 https://doi.org/10.1038/nmeth.4193	journal	February 2017
IL-12 p40 monomer is different from other IL-12 family members to selectively inhibit IL-12Rβ1 internalization and suppress EAE Mondal, Susanta; Kundu, Madhuchhanda; Jana, Malabendu Proceedings of the National Academy of Sciences, Vol. 117, Issue 35 https://doi.org/10.1073/pnas.2000653117	journal	August 2020
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
Tissue-based map of the human proteome Uhlen, M.; Fagerberg, L.; Hallstrom, B. M. Science, Vol. 347, Issue 6220 https://doi.org/10.1126/science.1260419	journal	January 2015
IL-21 induces IL-22 production in CD4+ T cells Yeste, Ada; Mascanfroni, Ivan D.; Nadeau, Meghan Nature Communications, Vol. 5, Issue 1 https://doi.org/10.1038/ncomms4753	journal	May 2014
Clinical Trials: IL-12 Deaths: Explanation and a Puzzle Cohen, J. Science, Vol. 270, Issue 5238 https://doi.org/10.1126/science.270.5238.908a	journal	November 1995
Gctf: Real-time CTF determination and correction Zhang, Kai Journal of Structural Biology, Vol. 193, Issue 1 https://doi.org/10.1016/j.jsb.2015.11.003	journal	January 2016
Administration of two macrophage-derived interferon-γ-inducing factors (IL-12 and IL-15) induces a lethal systemic inflammatory response in mice that is dependent on natural killer cells but does not require interferon-γ Biber, Jennifer L.; Jabbour, Saad; Parihar, Robin Cellular Immunology, Vol. 216, Issue 1-2 https://doi.org/10.1016/S0008-8749(02)00501-4	journal	March 2002
Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy Momin, Noor; Mehta, Naveen K.; Bennett, Nitasha R. Science Translational Medicine, Vol. 11, Issue 498 https://doi.org/10.1126/scitranslmed.aaw2614	journal	June 2019
IL-2 Modulates the TCR Signaling Threshold for CD8 but Not CD4 T Cell Proliferation on a Single-Cell Level Au-Yeung, Byron B.; Smith, Geoffrey Alexander; Mueller, James L. The Journal of Immunology, Vol. 198, Issue 6 https://doi.org/10.4049/jimmunol.1601453	journal	February 2017
The composition and signaling of the IL-35 receptor are unconventional Collison, Lauren W.; Delgoffe, Greg M.; Guy, Clifford S. Nature Immunology, Vol. 13, Issue 3 https://doi.org/10.1038/ni.2227	journal	February 2012
The Antibody-Based Delivery of Interleukin-12 to the Tumor Neovasculature Eradicates Murine Models of Cancer in Combination with Paclitaxel Pasche, Nadine; Wulhfard, Sarah; Pretto, Francesca Clinical Cancer Research, Vol. 18, Issue 15 https://doi.org/10.1158/1078-0432.CCR-12-0282	journal	June 2012
Substantial Energetic Improvement with Minimal Structural Perturbation in a High Affinity Mutant Antibody Midelfort, K. S.; Hernandez, H. H.; Lippow, S. M. Journal of Molecular Biology, Vol. 343, Issue 3 https://doi.org/10.1016/j.jmb.2004.08.019	journal	October 2004
Non-Canonical Interleukin 23 Receptor Complex Assembly Schröder, Jutta; Moll, Jens M.; Baran, Paul Journal of Biological Chemistry, Vol. 290, Issue 1 https://doi.org/10.1074/jbc.M114.617597	journal	January 2015
The Lipid Binding Pleckstrin Homology Domain in UNC-104 Kinesin is Necessary for Synaptic Vesicle Transport in Caenorhabditis elegans Klopfenstein, Dieter R.; Vale, Ronald D. Molecular Biology of the Cell, Vol. 15, Issue 8 https://doi.org/10.1091/mbc.e04-04-0326	journal	August 2004
The Structure of Interleukin-23 Reveals the Molecular Basis of p40 Subunit Sharing with Interleukin-12 Lupardus, Patrick J.; Garcia, K. Christopher Journal of Molecular Biology, Vol. 382, Issue 4 https://doi.org/10.1016/j.jmb.2008.07.051	journal	October 2008
IL-23 Receptor Expression on γδ T Cells Correlates with Their Enhancing or Suppressive Effects on Autoreactive T Cells in Experimental Autoimmune Uveitis Liang, Dongchun; Zuo, Aijun; Shao, Hui The Journal of Immunology, Vol. 191, Issue 3 https://doi.org/10.4049/jimmunol.1300626	journal	June 2013
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Interleukin 23 in the skin: role in psoriasis pathogenesis and selective interleukin 23 blockade as treatment Chan, Tom C.; Hawkes, Jason E.; Krueger, James G. Therapeutic Advances in Chronic Disease, Vol. 9, Issue 5 https://doi.org/10.1177/2040622318759282	journal	March 2018
IL-12 regulates the expansion, phenotype, and function of murine NK cells activated by IL-15 and IL-18 Oka, Naoto; Markova, Tzvetanka; Tsuzuki, Kenzo Cancer Immunology, Immunotherapy, Vol. 69, Issue 9 https://doi.org/10.1007/s00262-020-02553-4	journal	April 2020
Interleukin-12 and the regulation of innate resistance and adaptive immunity Trinchieri, Giorgio Nature Reviews Immunology, Vol. 3, Issue 2 https://doi.org/10.1038/nri1001	journal	February 2003
BacMam system for high-level expression of recombinant soluble and membrane glycoproteins for structural studies Dukkipati, Abhiram; Park, Hyun Ho; Waghray, Deepa Protein Expression and Purification, Vol. 62, Issue 2 https://doi.org/10.1016/j.pep.2008.08.004	journal	December 2008
Intratumoral Delivery of Interleukin 12 Expression Plasmids with In Vivo Electroporation Is Effective for Colon and Renal Cancer Tamura, Takahiko; Nishi, Toru; Goto, Tomoaki Human Gene Therapy, Vol. 12, Issue 10 https://doi.org/10.1089/104303401750270922	journal	July 2001
IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways Zhou, Liang; Ivanov, Ivaylo I.; Spolski, Rosanne Nature Immunology, Vol. 8, Issue 9 https://doi.org/10.1038/ni1488	journal	June 2007
Fiji: an open-source platform for biological-image analysis Schindelin, Johannes; Arganda-Carreras, Ignacio; Frise, Erwin Nature Methods, Vol. 9, Issue 7 https://doi.org/10.1038/nmeth.2019	journal	June 2012
Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning Pegram, Hollie J.; Lee, James C.; Hayman, Erik G. Blood, Vol. 119, Issue 18 https://doi.org/10.1182/blood-2011-12-400044	journal	May 2012
WSX-1 and Glycoprotein 130 Constitute a Signal-Transducing Receptor for IL-27 Pflanz, Stefan; Hibbert, Linda; Mattson, Jeanine The Journal of Immunology, Vol. 172, Issue 4 https://doi.org/10.4049/jimmunol.172.4.2225	journal	February 2004
IL-23 Is Critical in the Induction but Not in the Effector Phase of Experimental Autoimmune Encephalomyelitis Thakker, Paresh; Leach, Michael W.; Kuang, Wen The Journal of Immunology, Vol. 178, Issue 4 https://doi.org/10.4049/jimmunol.178.4.2589	journal	February 2007
The inhibitory cytokine IL-35 contributes to regulatory T-cell function Collison, Lauren W.; Workman, Creg J.; Kuo, Timothy T. Nature, Vol. 450, Issue 7169 https://doi.org/10.1038/nature06306	journal	November 2007
Hexameric Structure and Assembly of the Interleukin-6/IL-6 -Receptor/gp130 Complex Boulanger, M. J. Science, Vol. 300, Issue 5628 https://doi.org/10.1126/science.1083901	journal	June 2003
Interleukin 12: still a promising candidate for tumor immunotherapy? Lasek, Witold; Zagożdżon, Radosław; Jakobisiak, Marek Cancer Immunology, Immunotherapy, Vol. 63, Issue 5 https://doi.org/10.1007/s00262-014-1523-1	journal	February 2014
IL-23 is essential for T cell–mediated colitis and promotes inflammation via IL-17 and IL-6 Yen, David; Cheung, Jeanne; Scheerens, Heleen Journal of Clinical Investigation, Vol. 116, Issue 5 https://doi.org/10.1172/JCI21404	journal	May 2006
Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-γ production and STAT-mediated signal transduction Carson, William E.; Dierksheide, Julie E.; Jabbour, Saad Blood, Vol. 96, Issue 4 https://doi.org/10.1182/blood.V96.4.1465.h8001465_1465_1473	journal	August 2000
Structural Organization of a Full-Length gp130/LIF-R Cytokine Receptor Transmembrane Complex Skiniotis, Georgios; Lupardus, Patrick J.; Martick, Monika Molecular Cell, Vol. 31, Issue 5 https://doi.org/10.1016/j.molcel.2008.08.011	journal	September 2008
Cytokine therapy reverses NK cell anergy in MHC-deficient tumors Ardolino, Michele; Azimi, Camillia S.; Iannello, Alexandre Journal of Clinical Investigation, Vol. 124, Issue 11 https://doi.org/10.1172/JCI74337	journal	October 2014
A functional interleukin 12 receptor complex is composed of two -type cytokine receptor subunits Presky, D. H.; Yang, H.; Minetti, L. J. Proceedings of the National Academy of Sciences, Vol. 93, Issue 24 https://doi.org/10.1073/pnas.93.24.14002	journal	November 1996
Clinical improvement in psoriasis with specific targeting of interleukin-23 Kopp, Tamara; Riedl, Elisabeth; Bangert, Christine Nature, Vol. 521, Issue 7551 https://doi.org/10.1038/nature14175	journal	March 2015
Role of Interferon-γ in Mediating the Antitumor Efficacy of Interleukin-12 Brunda, Michael J.; Luistro, Leopoldo; Hendrzak, Jill A. Journal of Immunotherapy, Vol. 17, Issue 2 https://doi.org/10.1097/00002371-199502000-00001	journal	January 1995
IL-12 Deaths: Explanation and a Puzzle Cohen, Jon Science, Vol. 270, Issue 5238 https://doi.org/10.1126/science.270.5238.908.a	journal	November 1995

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structural biology
signaling

Title: Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells

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