This content will become publicly available on July 9, 2020
Structural insight into T cell coinhibition by PD-1H (VISTA)
Abstract
Programmed death-1 homolog (PD-1H), a CD28/B7 family molecule, coinhibits T cell activation and is an attractive immunotherapeutic target for cancer and inflammatory diseases. The molecular basis of its function, however, is unknown. Bioinformatic analyses indicated that PD-1H has a very long Ig variable region (IgV)-like domain and extraordinarily high histidine content, suggesting that unique structural features may contribute to coinhibitory mechanisms. Here we present the 1.9-Å crystal structure of the human PD-1H extracellular domain. It reveals an elongated CC′ loop and a striking concentration of histidine residues, located in the complementarity-determining region-like proximal half of the molecule. We show that surface-exposed histidine clusters are essential for robust inhibition of T cell activation. PD-1H exhibits a noncanonical IgV-like topology including an extra “H” β-strand and “clamping” disulfide, absent in known IgV-like structures, that likely restricts its orientation on the cell surface differently from other IgV-like domains. These results provide important insight into a molecular basis of T cell coinhibition by PD-1H.
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1582072
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Published Article
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 117 Journal Issue: 3; Journal ID: ISSN 0027-8424
- Publisher:
- Proceedings of the National Academy of Sciences
- Country of Publication:
- United States
- Language:
- English
Citation Formats
Slater, Benjamin T., Han, Xue, Chen, Lieping, and Xiong, Yong. Structural insight into T cell coinhibition by PD-1H (VISTA). United States: N. p., 2020.
Web. doi:10.1073/pnas.1908711117.
Slater, Benjamin T., Han, Xue, Chen, Lieping, & Xiong, Yong. Structural insight into T cell coinhibition by PD-1H (VISTA). United States. doi:10.1073/pnas.1908711117.
Slater, Benjamin T., Han, Xue, Chen, Lieping, and Xiong, Yong. Thu .
"Structural insight into T cell coinhibition by PD-1H (VISTA)". United States. doi:10.1073/pnas.1908711117.
@article{osti_1582072,
title = {Structural insight into T cell coinhibition by PD-1H (VISTA)},
author = {Slater, Benjamin T. and Han, Xue and Chen, Lieping and Xiong, Yong},
abstractNote = {Programmed death-1 homolog (PD-1H), a CD28/B7 family molecule, coinhibits T cell activation and is an attractive immunotherapeutic target for cancer and inflammatory diseases. The molecular basis of its function, however, is unknown. Bioinformatic analyses indicated that PD-1H has a very long Ig variable region (IgV)-like domain and extraordinarily high histidine content, suggesting that unique structural features may contribute to coinhibitory mechanisms. Here we present the 1.9-Å crystal structure of the human PD-1H extracellular domain. It reveals an elongated CC′ loop and a striking concentration of histidine residues, located in the complementarity-determining region-like proximal half of the molecule. We show that surface-exposed histidine clusters are essential for robust inhibition of T cell activation. PD-1H exhibits a noncanonical IgV-like topology including an extra “H” β-strand and “clamping” disulfide, absent in known IgV-like structures, that likely restricts its orientation on the cell surface differently from other IgV-like domains. These results provide important insight into a molecular basis of T cell coinhibition by PD-1H.},
doi = {10.1073/pnas.1908711117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 3,
volume = 117,
place = {United States},
year = {2020},
month = {1}
}
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Works referenced in this record:
Small-Molecule Immune Checkpoint Inhibitors Targeting PD-1/PD-L1 and Other Emerging Checkpoint Pathways
journal, August 2018
- Sasikumar, Pottayil G.; Ramachandra, Murali
- BioDrugs, Vol. 32, Issue 5
PD-1 Upregulated on Regulatory T Cells during Chronic Virus Infection Enhances the Suppression of CD8 + T Cell Immune Response via the Interaction with PD-L1 Expressed on CD8 + T Cells
journal, May 2015
- Park, Hyo Jin; Park, Joon Seok; Jeong, Yun Hee
- The Journal of Immunology, Vol. 194, Issue 12
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
journal, May 1997
- Murshudov, G. N.; Vagin, A. A.; Dodson, E. J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3
Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses
journal, March 2001
- Stamper, Carin C.; Zhang, Yan; Tobin, James F.
- Nature, Vol. 410, Issue 6828
Dali server update
journal, April 2016
- Holm, Liisa; Laakso, Laura M.
- Nucleic Acids Research, Vol. 44, Issue W1
Structural basis for co-stimulation by the human CTLA-4/B7-2 complex
journal, March 2001
- Schwartz, Jean-Claude D.; Zhang, Xuewu; Fedorov, Alexander A.
- Nature, Vol. 410, Issue 6828
VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses
journal, March 2011
- Wang, Li; Rubinstein, Rotem; Lines, Janet L.
- The Journal of Experimental Medicine, Vol. 208, Issue 3
Cutting Edge: A Monoclonal Antibody Specific for the Programmed Death-1 Homolog Prevents Graft-versus-Host Disease in Mouse Models
journal, July 2011
- Flies, Dallas B.; Wang, Shengdian; Xu, Haiying
- The Journal of Immunology, Vol. 187, Issue 4
Likelihood-enhanced fast rotation functions
journal, February 2004
- Storoni, Laurent C.; McCoy, Airlie J.; Read, Randy J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 3
The Crystal Structure of the Extracellular Domain of the Inhibitor Receptor Expressed on Myeloid Cells IREM-1
journal, March 2007
- Márquez, José Antonio; Galfré, Elena; Dupeux, Florine
- Journal of Molecular Biology, Vol. 367, Issue 2
Structural Basis of the CD8αβ/MHC Class I Interaction: Focused Recognition Orients CD8β to a T Cell Proximal Position
journal, July 2009
- Wang, Rui; Natarajan, Kannan; Margulies, David H.
- The Journal of Immunology, Vol. 183, Issue 4
Cell Surface Signaling Molecules in the Control of Immune Responses: A Tide Model
journal, April 2011
- Zhu, Yuwen; Yao, Sheng; Chen, Lieping
- Immunity, Vol. 34, Issue 4
TIM-1 and TIM-4 Glycoproteins Bind Phosphatidylserine and Mediate Uptake of Apoptotic Cells
journal, December 2007
- Kobayashi, Norimoto; Karisola, Piia; Peña-Cruz, Victor
- Immunity, Vol. 27, Issue 6
Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype with predisposition to the development of autoimmunity
journal, September 2014
- Wang, L.; Le Mercier, I.; Putra, J.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 41
Diversity in the CDR3 Region of VH Is Sufficient for Most Antibody Specificities
journal, July 2000
- Xu, John L.; Davis, Mark M.
- Immunity, Vol. 13, Issue 1
Neuron-specific SALM5 limits inflammation in the CNS via its interaction with HVEM
journal, April 2016
- Zhu, Yuwen; Yao, Sheng; Augustine, Mathew M.
- Science Advances, Vol. 2, Issue 4
Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53
journal, July 2015
- Yoon, K. W.; Byun, S.; Kwon, E.
- Science, Vol. 349, Issue 6247
Acidic extracellular microenvironment and cancer
journal, January 2013
- Kato, Yasumasa; Ozawa, Shigeyuki; Miyamoto, Chihiro
- Cancer Cell International, Vol. 13, Issue 1
A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization
journal, October 2018
- Sanmamed, Miguel F.; Chen, Lieping
- Cell, Vol. 175, Issue 2
VISTA Regulates the Development of Protective Antitumor Immunity
journal, March 2014
- Le Mercier, I.; Chen, W.; Lines, J. L.
- Cancer Research, Vol. 74, Issue 7
Structures of T Cell Immunoglobulin Mucin Protein 4 Show a Metal-Ion-Dependent Ligand Binding Site where Phosphatidylserine Binds
journal, December 2007
- Santiago, César; Ballesteros, Angela; Martínez-Muñoz, Laura
- Immunity, Vol. 27, Issue 6
Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis
journal, May 2017
- Li, Na; Xu, Wenwen; Yuan, Ying
- Scientific Reports, Vol. 7, Issue 1
The Buccaneer software for automated model building. 1. Tracing protein chains
journal, August 2006
- Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 9
The multiple roles of histidine in protein interactions
journal, March 2013
- Liao, Si-Ming; Du, Qi-Shi; Meng, Jian-Zong
- Chemistry Central Journal, Vol. 7, Issue 1
The Pfam protein families database in 2019
journal, October 2018
- El-Gebali, Sara; Mistry, Jaina; Bateman, Alex
- Nucleic Acids Research, Vol. 47, Issue D1
Initiation of T cell signaling by CD45 segregation at 'close contacts'
journal, March 2016
- Chang, Veronica T.; Fernandes, Ricardo A.; Ganzinger, Kristina A.
- Nature Immunology, Vol. 17, Issue 5
Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell–mediated immunity
journal, April 2014
- Flies, Dallas B.; Han, Xue; Higuchi, Tomoe
- Journal of Clinical Investigation, Vol. 124, Issue 5
Deciphering key features in protein structures with the new ENDscript server
journal, April 2014
- Robert, Xavier; Gouet, Patrice
- Nucleic Acids Research, Vol. 42, Issue W1
Blocking the VISTA pathway enhances disease progression in (NZB × NZW) F1 female mice
journal, June 2017
- Sergent, Pa; Plummer, Sf; Pettus, J.
- Lupus, Vol. 27, Issue 2
VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer
journal, March 2017
- Gao, Jianjun; Ward, John F.; Pettaway, Curtis A.
- Nature Medicine, Vol. 23, Issue 5
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis
journal, September 2003
- Clements, C. S.; Reid, H. H.; Beddoe, T.
- Proceedings of the National Academy of Sciences, Vol. 100, Issue 19
Treatment of Rheumatoid Arthritis by Selective Inhibition of T-Cell Activation with Fusion Protein CTLA4Ig
journal, November 2003
- Kremer, Joel M.; Westhovens, Rene; Leon, Marc
- New England Journal of Medicine, Vol. 349, Issue 20
VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis
journal, March 2017
- Ceeraz, Sabrina; Sergent, Petra A.; Plummer, Sean F.
- Arthritis & Rheumatology, Vol. 69, Issue 4
Molecular mechanisms of T cell co-stimulation and co-inhibition
journal, March 2013
- Chen, Lieping; Flies, Dallas B.
- Nature Reviews Immunology, Vol. 13, Issue 4
Structural Basis of Inducible Costimulator Ligand Costimulatory Function: Determination of the Cell Surface Oligomeric State and Functional Mapping of the Receptor Binding Site of the Protein
journal, September 2006
- Chattopadhyay, Kausik; Bhatia, Sumeena; Fiser, Andras
- The Journal of Immunology, Vol. 177, Issue 6
Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity
journal, May 2004
- Chen, Lieping
- Nature Reviews Immunology, Vol. 4, Issue 5
NMRPipe: A multidimensional spectral processing system based on UNIX pipes
journal, November 1995
- Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW.
- Journal of Biomolecular NMR, Vol. 6, Issue 3
Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy
journal, March 2019
- Wang, Jun; Sun, Jingwei; Liu, Linda N.
- Nature Medicine, Vol. 25, Issue 4
Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses
journal, May 2015
- Liu, Jun; Yuan, Ying; Chen, Wenna
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 21
The tyrosine corner: A feature of most greek key β-barrel proteins
journal, November 1994
- Hemmingsen, Jens M.; Gernert, Kim M.; Richardson, Jane S.
- Protein Science, Vol. 3, Issue 11
Crystal structure of a soluble CD28-Fab complex
journal, February 2005
- Evans, Edward J.; Esnouf, Robert M.; Manso-Sancho, Raquel
- Nature Immunology, Vol. 6, Issue 3
The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors
journal, February 2008
- Lin, D. Y. -w.; Tanaka, Y.; Iwasaki, M.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 8
Evolution of the B7 family: co-evolution of B7H6 and NKp30, identification of a new B7 family member, B7H7, and of B7's historical relationship with the MHC
journal, April 2012
- Flajnik, Martin F.; Tlapakova, Tereza; Criscitiello, Michael F.
- Immunogenetics, Vol. 64, Issue 8
A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma
journal, May 2017
- Liu, Huafeng; Li, Xin; Hu, Li
- Cellular & Molecular Immunology, Vol. 15, Issue 9
Costimulation Blockade with Belatacept in Renal Transplantation
journal, August 2005
- Vincenti, Flavio; Larsen, Christian; Durrbach, Antoine
- New England Journal of Medicine, Vol. 353, Issue 8
High resolution X-ray and NMR structural study of human T-cell immunoglobulin and mucin domain containing protein-3
journal, November 2018
- Gandhi, Amit K.; Kim, Walter M.; Sun, Zhen-Yu J.
- Scientific Reports, Vol. 8, Issue 1