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Molecular Mechanisms Of T Cell Co-stimulation And Co-inhibition
L. Chen, D. Flies
Published 2013 · Biology, Medicine
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Co-stimulatory and co-inhibitory receptors have a pivotal role in T cell biology, as they determine the functional outcome of T cell receptor (TCR) signalling. The classic definition of T cell co-stimulation continues to evolve through the identification of new co-stimulatory and co-inhibitory receptors, the biochemical characterization of their downstream signalling events and the delineation of their immunological functions. Notably, it has been recently appreciated that co-stimulatory and co-inhibitory receptors display great diversity in expression, structure and function, and that their functions are largely context dependent. Here, we focus on some of these emerging concepts and review the mechanisms through which T cell activation, differentiation and function is controlled by co-stimulatory and co-inhibitory receptors.
This paper references
CD28 and CTLA‐4 coreceptor expression and signal transduction
C. Rudd (2009)
Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses.
M. Butte (2007)
Ligation of B7-1/B7-2 by Human CD4+ T Cells Triggers Indoleamine 2,3-Dioxygenase Activity in Dendritic Cells1
D. Munn (2004)
The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation
M. Steinberg (2011)
Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2
E. Lázár-Molnár (2008)
Regulatory T Cell Expression of Herpesvirus Entry Mediator Suppresses the Function of B and T Lymphocyte Attenuator-Positive Effector T Cells1
R. Tao (2008)
B7 expression on T cells down-regulates immune responses through CTLA-4 ligation via T-T interactions [corrections].
P. Taylor (2004)
Immunobiology. Combined targeted and immunotherapy: the future of personalized medicine.
A. Marabelle (2012)
CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype.
Yuwen Zhu (2007)
Faculty Opinions recommendation of Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
P. Bousso (2011)
Dichotomous regulation of GVHD through bidirectional functions of the BTLA-HVEM pathway.
Y. Sakoda (2011)
Progressive Loss of Memory T Cell Potential and Commitment to Exhaustion during Chronic Viral Infection
Jill M. Angelosanto (2012)
The CD4-like molecule LAG-3, biology and therapeutic applications
S. Sierro (2011)
ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6.
Youn Soo Choi (2011)
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells
Loise M. Francisco (2009)
CTLA-4 is a second receptor for the B cell activation antigen B7
P. Linsley (1991)
Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease.
S. Paust (2004)
TCR-Independent CD30 Signaling Selectively Induces IL-13 Production Via a TNF Receptor-Associated Factor/p38 Mitogen-Activated Protein Kinase-Dependent Mechanism1
H. Harlin (2002)
Regulation of costimulation in the era of butyrophilins.
H. Arnett (2009)
LAIR and collagens in immune regulation.
L. Meyaard (2010)
Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions
K. Curran (2012)
The Programmed Death-1 Ligand 1:B7-1 Pathway Restrains Diabetogenic Effector T Cells In Vivo
A. Paterson (2011)
TNF superfamily in inflammatory disease: translating basic insights.
M. Croft (2012)
During Viral Infection of the Respiratory Tract, CD27, 4-1BB, and OX40 Collectively Determine Formation of CD8+ Memory T Cells and Their Capacity for Secondary Expansion1
J. Hendriks (2005)
B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance.
Jang-June Park (2010)
Bimodal regulation of T cell-mediated immune responses by TIM-4.
M. Mizui (2008)
ICOS Ligation Recruits the p50α PI3K Regulatory Subunit to the Immunological Synapse1
Camille Fos (2008)
Differential T cell costimulatory requirements in CD28-deficient mice.
A. Shahinian (1993)
Positive and negative signaling through SLAM receptors regulate synapse organization and thresholds of cytolysis.
F. Zhao (2012)
Synergistic T cell activation via the physiological ligands for CD2 and the T cell receptor
B. Bierer (1988)
PD‐1 inhibits T‐cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ
K. Sheppard (2004)
expression and function
K. S. Hathcock (1994)
Current Understanding and Future Directions for Vocal Fold Mechanobiology.
N. Y. Li (2013)
Biochemical and Genetic Evidence for a SAP-PKC-θ Interaction Contributing to IL-4 Regulation
J. Cannons (2010)
Immune regulation by 4‐1BB and 4‐1BBL: complexities and challenges
C. Wang (2009)
Functional Exhaustion of CD4+ T Lymphocytes during Primary Cytomegalovirus Infection
P. Antoine (2012)
Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS).
Tyler R. Simpson (2010)
Role of CD27/CD70 pathway of activation in immunity and tolerance
J. Denoeud (2011)
keys to effective T-cell immunity? Nature Rev
Transcription factor regulation of CD8+ T‐cell memory and exhaustion
Jill M. Angelosanto (2010)
B70 antigen is a second ligand for CTLA-4 and CD28
M. Azuma (1993)
B7 Expression on T Cells Down-Regulates Immune Responses through CTLA-4 Ligation via R-T Interactions1
P. Taylor (2004)
T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1.
P. Linsley (1990)
Bcl6 and Maf Cooperate To Instruct Human Follicular Helper CD4 T Cell Differentiation
Mark A. Kroenke (2012)
Letter: The use of the cell migration inhibition test.
Spitler Le (1974)
Regulating the regulators: costimulatory signals control the homeostasis and function of regulatory T cells
Hélène Bour-Jordan (2009)
Tim‐4 inhibition of T‐cell activation and T helper type 17 differentiation requires both the immunoglobulin V and mucin domains and occurs via the mitogen‐activated protein kinase pathway
W. Cao (2011)
B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator
J. Sedy (2005)
HVEM/LIGHT/BTLA/CD160 cosignaling pathways as targets for immune regulation
M. L. Rio (2010)
Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory.
Travis A. Doering (2012)
T cell clonal anergy.
R. Schwartz (1997)
Memory T cells need CD28 costimulation to remember.
A. Boesteanu (2009)
B7-h2 is a costimulatory ligand for CD28 in human.
S. Yao (2011)
New Insights on OX40 in the Control of T Cell Immunity and Immune Tolerance In Vivo
X. Xiao (2012)
The PDL1-PD1 Axis Converts Human TH1 Cells into Regulatory T Cells
S. Amarnath (2011)
Differential Requirement of ZAP-70 for CD2-Mediated Activation Pathways of Mature Human T Cells1
E. Meinl (2000)
T Cell Ig and Mucin Domain Proteins and Immunity
L. Kane (2010)
Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS
S. Wang (2000)
Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2
T. Yokosuka (2012)
versatile platforms for cancer immunotherapy
L. M. Weiner (2010)
LAG-3 in Cancer Immunotherapy.
Monica V. Goldberg (2011)
Dynamic regulation of T cell activation and co‐stimulation through TCR‐microclusters
T. Saito (2010)
Negative feedback of T cell activation through inhibitory adapters and costimulatory receptors
T. Saito (2003)
Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA.
Maya Gavrieli (2006)
Migration of Th1 Lymphocytes Is Regulated by CD152 (CTLA-4)-Mediated Signaling via PI3 Kinase-Dependent Akt Activation
Karin Knieke (2012)
The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro
K. Inaba (1994)
Complexities and Challenges in Managed Care
William J. Cardarelli (2008)
The B7 family revisited.
R. Greenwald (2005)
Combating chronic T-cell exhaustion.
M. McAfee (2012)
HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria
Jr-Wen Shui (2012)
The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses
L. Walker (2011)
Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2.
Maya Gavrieli (2003)
T-cell co-stimulation through B7RP-1 and ICOS
S. K. Yoshinaga (1999)
GITR: a modulator of immune response and inflammation.
G. Nocentini (2009)
Cutting Edge: A Monoclonal Antibody Specific for the Programmed Death-1 Homolog Prevents Graft-versus-Host Disease in Mouse Models
D. Flies (2011)
Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection
Chao Wang (2012)
Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase.
M. Sharma (2007)
Regulation of natural cytotoxicity by the adaptor SAP and the Src-related kinase Fyn
C. Bloch-Queyrat (2005)
The clinical utility of inhibiting CD28‐mediated costimulation
P. Linsley (2009)
Rational Development of LEA29Y (belatacept), a High‐Affinity Variant of CTLA4‐Ig with Potent Immunosuppressive Properties
C. Larsen (2005)
Sequence, structure, function, immunity: structural genomics of costimulation
Kausik Chattopadhyay (2009)
The role of TNF superfamily members in T-cell function and diseases
M. Croft (2009)
PD-1 and its ligands in tolerance and immunity.
M. Keir (2008)
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
S. Topalian (2012)
Future of Personalized Medicine
K. Jain (2009)
The blockade of immune checkpoints in cancer immunotherapy
D. Pardoll (2012)
VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses
L. Wang (2011)
Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.
G. Suntharalingam (2006)
CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1.
J. Fourcade (2012)
a tide model
Y. Zhu (2011)
Monoclonal antibodies: versatile platforms for cancer immunotherapy
L. Weiner (2010)
T cell anergy.
R. Schwartz (1993)
Receptors that interact with nectin and nectin-like proteins in the immunosurveillance and immunotherapy of cancer.
C. J. Chan (2012)
RELT, a new member of the tumor necrosis factor receptor superfamily, is selectively expressed in hematopoietic tissues and activates transcription factor NF-kappaB.
G. Sica (2001)
Cancer immunotherapy comes of age
I. Mellman (2011)
translating basic insights
a bidirectional switch regulating T-cell activation
G. Cai (2009)
Combining immunotherapy and targeted therapies in cancer treatment
M. Vanneman (2012)
T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression.
C. June (1987)
Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell-Extrinsic Function of CTLA-4
O. Qureshi (2011)
Comparative analysis of B7-1 and B7-2 costimulatory ligands: expression and function
K. Hathcock (1994)
An enigmatic tail of CD28 signaling.
J. Boomer (2010)
Control of peripheral T‐cell tolerance and autoimmunity via the CTLA‐4 and PD‐1 pathways
B. Fife (2008)
A new analysis of allogeneic interactions.
K. Lafferty (1975)
CD30—Governor of Memory T Cells?
E. Podack (2002)
Comparative Analysis of B 7-1 and B 7-2 Costimulatory Ligands : Expression and Function
K. Hathcock (2003)
Suppression of Allograft Rejection by Tim-1-Fc through Cross-Linking with a Novel Tim-1 Binding Partner on T Cells
L. Xiao (2011)
SLAM family receptors and SAP adaptors in immunity.
J. Cannons (2011)
PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV.
D. Franceschini (2009)
a monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models
D. B. Flies (2011)
Coexpression of PD-1, 2B4, CD160 and KLRG1 on Exhausted HCV-Specific CD8+ T Cells Is Linked to Antigen Recognition and T Cell Differentiation
B. Bengsch (2010)
Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation.
T. Yokosuka (2010)
Early CD30 signaling is critical for adoptively transferred CD4+CD25+ regulatory T cells in prevention of acute graft-versus-host disease.
R. Zeiser (2007)
Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS.
Michelle A. Linterman (2009)
A Theory of Self-Nonself Discrimination
P. Bretscher (1970)
Opportunities and challenges in the development of experimental drug combinations for cancer.
R. Humphrey (2011)
Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?
M. Croft (2003)
The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors
D. Y. Lin (2008)
Selective Effects of PD-1 on Akt and Ras Pathways Regulate Molecular Components of the Cell Cycle and Inhibit T Cell Proliferation
N. Patsoukis (2012)
The adaptor SAP controls NK cell activation by regulating the enzymes Vav-1 and SHIP-1 and by enhancing conjugates with target cells.
Z. Dong (2012)
Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy.
D. Mueller (1989)
Emerging Tim-3 functions in antimicrobial and tumor immunity.
Kaori Sakuishi (2011)
Regulatory T Cells and Human Myeloid Dendritic Cells Promote Tolerance via Programmed Death Ligand-1
S. Amarnath (2010)
Cell surface signaling molecules in the control of immune responses: a tide model.
Yuwen Zhu (2011)
The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T‐cell activation
G. Cai (2009)
Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling
C. Rudd (2003)
An improved understanding of TNFL/TNFR interactions using structure-based classifications.
C. Magis (2012)
structural genomics of costimulation
Identification of an alternative CTLA-4 ligand costimulatory for T cell activation.
K. Hathcock (1993)
Timing and tuning of CD27–CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology
M. Nolte (2009)
The role of OX40-mediated co-stimulation in T-cell activation and survival.
William L. Redmond (2009)
The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development.
R. Kageyama (2012)
SLAM receptors and SAP influence lymphocyte interactions, development and function
P. Schwartzberg (2009)
PD‐1 signaling in primary T cells
J. Riley (2009)
Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors
S. Takamura (2010)
The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans
Cameron S. Brandt (2009)
Coordinate Regulation of T Cell Activation by CD2 and CD281
J. Green (2000)
Evidence Implicating the Ras Pathway in Multiple CD28 Costimulatory Functions in CD4+ T Cells
Sujit V. Janardhan (2011)
The Adaptor Protein TRADD Is Essential for TNF-Like Ligand 1A/Death Receptor 3 Signaling
Yelena L Pobezinskaya (2011)
A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator.
L. A. Gonzalez (2005)
Ligands working as receptors: reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system.
G. Eissner (2004)
B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells.
T. Azuma (2008)
T cell exhaustion
E. Wherry (2011)
OX40 signaling favors the induction of TH9 cells and airway inflammation
X. Xiao (2012)
Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies.
P. Ascierto (2010)
Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion
M. Rangachari (2012)
TL1A and DR3, a TNF family ligand‐receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation
F. Meylan (2011)
MODULATING CO-STIMULATION DURING ANTIGEN PRESENTATION TO ENHANCE CANCER IMMUNOTHERAPY.
T. Liechtenstein (2012)
Extended Co-Expression of Inhibitory Receptors by Human CD8 T-Cells Depending on Differentiation, Antigen-Specificity and Anatomical Localization
Lukas Baitsch (2012)
This paper is referenced by
CD5 signalosome coordinates antagonist TCR signals to control the generation of Treg cells induced by foreign antigens
Gaëtan Blaize (2020)
The Role of the HIV-1 Accessory Proteins Nef and Vpu in Subverting Host Cellular Immunity
Emily N. Pawlak (2018)
Title : From monoclonal antibodies to small molecules : the development of inhibitors targeting the PD-1 / PD-L 1 pathway
Mei-Miao Zhan (2016)
Intratumoral STING Activation Sensitizes Poorly Immunogenic Cancers to Checkpoint Blockade Immunotherapy
Casey R. Ager (2018)
Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes
Michael Steven Rooney (2015)
B7 Family Proteins in Cancer Progression: Immunological and Non-Immunological Functions
Qin Ye (2019)
Beyond PD-1/PD-L1 Axis Blockade: New Combination Strategies in Metastatic Melanoma Treatment
Emilio Francesco Giunta (2019)
A Quantitative Multivariate Model of Human Dendritic Cell-T Helper Cell Communication
M. Grandclaudon (2019)
Programmed death-ligand-1 expression in advanced gastric cancer detected with RNA in situ hybridization and its clinical significance
J. Yuan (2016)
Structural insight into T cell coinhibition by PD-1H (VISTA)
Benjamin T Slater (2020)
The immunoinhibitory PD‐1/PD‐L1 pathway in inflammatory blood vessel disease
C. Weyand (2018)
Malignant inflammation in cutaneous T‐cell lymphoma—a hostile takeover
T. Krejsgaard (2016)
Orchestrating immune check-point blockade for cancer immunotherapy in combinations.
J. Pérez-Gracia (2014)
Microneedles for Gene Therapy: Overcoming Extracellular and Intracellular Barriers
G. Cole (2018)
A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis
Eleanor A Fallon (2018)
Regulatory roles of IL-10–producing human follicular T cells
Pablo F Cañete (2019)
Association of OX40 gene polymorphisms (rs17568G/A and rs229811A/C) with head and neck squamous cell carcinoma
Z. Faghih (2019)
Associations between the cytotoxic T lymphocyte antigen 4 polymorphisms and risk of bone sarcomas
Changchun Fan (2014)
Charting Immune Signaling Proteomes En Route to New Therapeutic Strategies
E. Haura (2015)
Constitutive expression of NF-κB inducing kinase in regulatory T cells impairs suppressive function and promotes instability and pro-inflammatory cytokine production
Fanny Polesso (2017)
Interaction of CD99 and its ligand upregulates IL-6 and TNF-α upon T cell activation
Nuchjira Takheaw (2019)
Tipping the balance: inhibitory checkpoints in intestinal homeostasis
M. Joosse (2018)
Immune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled
J. P. Bewersdorf (2019)
Pembrolizumab for the first-line treatment of non-small cell lung cancer
K. Ninomiya (2018)
Triggering of CD99 on monocytes by a specific monoclonal antibody regulates T cell activation.
Witida Laopajon (2019)
Functional crosstalk between T cells and monocytes in cancer and atherosclerosis
Lindsey E Padgett (2020)
Immunotherapy Is Changing First-Line Treatment of Metastatic Renal-Cell Carcinoma.
M. Labriola (2019)
Overexpression of CD155 is associated with PD-1 and PD-L1 expression on immune cells, rather than tumor cells in the breast cancer microenvironment
Ruibin Wang (2020)
Modulation of hepatic stellate cells and reversibility of hepatic fibrosis
Y. Huang (2017)
Immunology and Immunotherapy in Ovarian Cancer
M. Mandai (2017)
Elevated T cell activation score is associated with improved survival of breast cancer
L. Lu (2017)
A CD200R-CD28 fusion protein appropriates an inhibitory signal to enhance T-cell function and therapy of murine leukemia.
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