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PD-1 signaling in primary T cells

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Riley, James L.·2009·Immunological Reviews

DOI 10.1111/j.1600-065x.2009.00767.xPMC PMC3424066

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Abstract

Summary: Programmed death‐1 (PD‐1) is a cell surface molecule that regulates the adaptive immune response. Engagement of PD‐1 by its ligands PD‐L1 or PD‐L2 transduces a signal that inhibits T‐cell proliferation, cytokine production, and cytolytic function. While a great deal is known concerning the biologic roles PD‐1 plays in regulating the primary immune response and in T‐cell exhaustion, comparatively little is known regarding how PD‐1 ligation alters signaling pathways. PD‐1 ligation is known to inhibit membrane‐proximal T‐cell signaling events, while ligation of the related inhibitory molecule cytotoxic T‐lymphocyte antigen‐4 appears to target more downstream signaling pathways. A major obstacle to an in‐depth understanding of PD‐1 signaling is the lack of physiologic models in which to study signal transduction. This review focuses on: (i) signaling pathways altered by PD‐1 ligation, (ii) factors recruited upon PD‐1 phosphorylation, and (iii) exploring the hypothesis that PD‐1 ligation induces distinct signals during various stages of immune‐cell differentiation. Lastly, we describe models to dissect the function of the PD‐1 cytoplasmic tail using primary cells in the absence of agonist antibodies.

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Background
Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 and CD8 T Cell-Mediated Alloimmune Responses In Vivo
Ito, T., Ueno, T., Clarkson, M. R., Yuan, X., Jurewicz, M. M., Yagita∥, H., Azuma, M., Sharpe, A. H., Auchincloss, H., Sayegh, M. H., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.11.6648 · Cited by 153
The membrane attack complex of complement induces caspase activation and apoptosis
Nauta, A. J., Daha, M. R., Tijsma, O., van de Water, B., Tedesco, F., & Roos, A. (2002) · European Journal of Immunology · doi:10.1002/1521-4141(200203)32:3 · Cited by 147
Involvement of SH2-containing Phosphotyrosine Phosphatase Syp in Erythropoietin Receptor Signal Transduction Pathways
Tauchi, T., Feng, G., Shen, R., Hoatlin, M. E., Bagby, G. C., Kabat, D., Lu, L., & Broxmeyer, H. E. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.10.5631 · Cited by 139 · cited 1×
“both the platelet-derived growth factor receptor (58) and”
Background
CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that inhibits interleukin-2 secretion but allows Bcl-X(L) induction.
Blair, P. J., Riley, J. L., Levine, B. L., Lee, K. P., Craighead, N., Francomano, T., Perfetto, S. J., Gray, G. S., Carreno, B. M., & June, C. H. (1998) · PubMed · Cited by 135
Self-citation
Growth Factor Receptor-bound Protein 2 SH2/SH3 Domain Binding to CD28 and Its Role in Co-signaling
Kim, H., Tharayil, M., & Rudd, C. E. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.1.296 · Cited by 135
Mutation of the SHP-2 Binding Site in Growth Hormone (GH) Receptor Prolongs GH-Promoted Tyrosyl Phosphorylation of GH Receptor, JAK2, and STAT5B
Stofega, M. R., Herrington, J. B., Billestrup, N., & Carter‐Su, C. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.9.0513 · Cited by 134 · cited 1×
“While much of the research on SHP-2 focuses on how it enhances cell activation, there is evidence that SHP-2 activation is involved in negative regulation of growth hormone and IL-6 signaling (62, 63) and natural killer (NK)-cell activation (64), suggesting that SHP-2 is also a viable candidate to mediate PD-1 immunos…”
Background
SHP-1- and Phosphotyrosine-Independent Inhibitory Signaling by a Killer Cell Ig-Like Receptor Cytoplasmic Domain in Human NK Cells
Yusa, S.-I., Catina, T. L., & Campbell, K. S. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.10.5047 · Cited by 132 · cited 1×
“While much of the research on SHP-2 focuses on how it enhances cell activation, there is evidence that SHP-2 activation is involved in negative regulation of growth hormone and IL-6 signaling (62, 63) and natural killer (NK)-cell activation (64), suggesting that SHP-2 is also a viable candidate to mediate PD-1 immunos…”
Background
Evidence That SHIP-1 Contributes to Phosphatidylinositol 3,4,5-Trisphosphate Metabolism in T Lymphocytes and Can Regulate Novel Phosphoinositide 3-Kinase Effectors
Freeburn, R. W., Wright, K. L., Burgess, S., Astoul, E., Cantrell, D. A., & Ward, S. G. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.10.5441 · Cited by 121
Ligation of CD28 receptor by B7 induces formation of D‐3 phosphoinositides in T lymphocytes independently of T cell receptor/CD3 activation
Ward, S. G., Westwick, J. K., Hall, N. D., & Sansom, D. M. (1993) · European Journal of Immunology · doi:10.1002/eji.1830231029 · Cited by 120 · cited 1×
“CD28 costimulation resulted in a strong induction of PI3K activity detected in immunoprecipitates in agreement with previous reports (41).”
Result
Cutting Edge: CTLA-4 Ligation Delivers a Unique Signal to Resting Human CD4 T Cells That Inhibits Interleukin-2 Secretion but Allows Bcl-XL Induction
Blair, P. J., Riley, J. L., Levine, B. L., Lee, K. P., Craighead, N., Francomano, T., Perfetto, S. J., Gray, G. S., Carreno, B. M., & June, C. H. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.1.12 · Cited by 118
Self-citation
Siglec-5 (CD170) Can Mediate Inhibitory Signaling in the Absence of Immunoreceptor Tyrosine-based Inhibitory Motif Phosphorylation
Avril, T., Freeman, S. D., Attrill, H. L., Clarke, R. G., & Crocker, P. R. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502041200 · Cited by 102 · cited 1×
“On the other hand, the ITSM is required for SHP-1 but not SHP-2 recruitment in Siglec cytoplasmic tails, consistent with the notion that SHP-1 may be the main effector in PD-1-mediated signaling (68).”
Background
A Single Amino Acid Alteration in Cytoplasmic Domain Determines IL-2 Promoter Activation by Ligation of CD28 but Not Inducible Costimulator (ICOS)
Harada, Y., Ohgai, D., Watanabe, R., Okano, K., Koiwai, O., Tanabe, K., Toma, H., Altman, A., & Abe, R. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021305 · Cited by 98
A Cell-Based Artificial Antigen-Presenting Cell Coated with Anti-CD3 and CD28 Antibodies Enables Rapid Expansion and Long-Term Growth of CD4 T Lymphocytes
Thomas, A., Maus, M. V., Shalaby, W. S. W., June, C. H., & Riley, J. L. (2002) · Clinical Immunology · doi:10.1006/clim.2002.5277 · Cited by 95 · cited 1×
“We chose the human erythromyeloid chronic myelogenous leukemia cell line K562 as a scaffold for these aAPCs, because they do not express human leukocyte antigen (HLA) proteins that would promote allogeneic responses, but they do express intracellular adhesion molecule (ICAM, CD54) and lymphocyte function antigen-3 (LF…”
Self-citation
Lentiviral Vectors Encoding Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Receptor Genes Efficiently Convert Peripheral Blood CD8 T Lymphocytes into Cytotoxic T Lymphocytes with Potent In Vitro and In Vivo HIV-1-Specific Inhibitory Activity
Joseph, A., Zheng, J., Follenzi, A., Dilorenzo, T., Sango, K., Hyman, J., Chen, K., Piechocka-Trocha, A., Brander, C., Hooijberg, E., et al. (2008) · Journal of Virology · doi:10.1128/jvi.01812-07 · Cited by 94
B and T Lymphocyte Attenuator-Mediated Signal Transduction Provides a Potent Inhibitory Signal to Primary Human CD4 T Cells That Can Be Initiated by Multiple Phosphotyrosine Motifs
Chemnitz, J. M., Lanfranco, A. R., Braunstein, I., & Riley, J. L. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.11.6603 · Cited by 87
Self-citation
Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA
Gavrieli, M., & Murphy, K. M. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.05.036 · Cited by 85 · cited 1×
“Furthermore, whether the motifs within the BTLA cytoplasmic tail actually recruit Grb2 or related molecules, or whether they are even important for BTLA function, is unclear (27, 28).”
Background
Investigations into the Regulation and Function of the SH2 Domain-Containing Protein-Tyrosine Phosphatase, SHP-1
Tsui, F. W. L., Martín, A., Wang, J., & Tsui, H. W. (2006) · Immunologic Research · doi:10.1385/ir:35:1:127 · Cited by 83 · cited 1×
“The specificity of each SH2 domain is largely determined by the three amino acids upstream of the tyrosine (51).”
Background
Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes
Harris, S. J., Parry, R. V., Westwick, J. K., & Ward, S. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.r700044200 · Cited by 81 · cited 1×
“Ship also binds to ITIMs and can inhibit PI3K activity (70).”
Background
Programmed Death 1 Ligand (PD-L) 1 and PD-L2 Limit Autoimmune Kidney Disease: Distinct Roles
Weinmann‐Menke, J., Lucas, J. A., Zeller, G. C., Keir, M. E., Huang, X. R., Tsuboi, N., Mayadas, T. N., Lan, H. Y., Sharpe, A. H., & Kelley, V. R. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.11.7466 · Cited by 81
Constitutive Association of SHP-1 with Leukocyte-Associated Ig-Like Receptor-1 in Human T Cells
Sathish, J. G., Johnson, K. G., FULLER, K. J., LeRoy, F. G., Meyaard, L., Sims, M., & Matthews, R. J. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.3.1763 · Cited by 75 · cited 15×
“Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation.”
BackgroundInfluential
Adapter Function of Protein-tyrosine Phosphatase 1D in Insulin Receptor/Insulin Receptor Substrate-1 Interaction
Kharitonenkov, A., Schnekenburger, J., Chen, Z., Knyazev, P. G., Ali, S., Zwick, E., White, M. F., & Ullrich, A. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.49.29189 · Cited by 75 · cited 1×
“tor substrate (IRS) to the insulin receptor (57) and Grb2 to”
Background
Grb2 Forms an Inducible Protein Complex with CD28 through a Src Homology 3 Domain-Proline Interaction
Okkenhaug, K., & Rottapel, R. K. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.33.21194 · Cited by 73
Leukocyte‐associated Ig‐like receptor‐1 has SH2 domain‐containing phosphatase‐independent function and recruits C‐terminal Src kinase
Verbrugge, A., Rijkers, E. S. K., Ruiter, T. E.-D., & Meyaard, L. (2005) · European Journal of Immunology · doi:10.1002/eji.200535226 · Cited by 68 · cited 2×
“By using a yeast tri-hybrid system, phosphorylated LAIR was found to bind Csk, suggesting that it plays a role in LAIR-mediated inhibition (74).”
BackgroundMethod
Systematic identification of immunoreceptor tyrosine-based inhibitory motifs in the human proteome
Staub, E., Rosenthal, A., & Hinzmann, B. (2003) · Cellular Signalling · doi:10.1016/j.cellsig.2003.08.013 · Cited by 64
Grb2 and Gads Exhibit Different Interactions with CD28 and Play Distinct Roles in CD28-Mediated Costimulation
Watanabe, R., Harada, Y., Takeda, K., Takahashi, J., Ohnuki, K., Ogawa, S., Ohgai, D., Kaibara, N., Koiwai, O., Tanabe, K., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.2.1085 · Cited by 62
GRID: A Novel Grb-2-Related Adapter Protein That Interacts with the Activated T Cell Costimulatory Receptor CD28
Ellis, J. H., Ashman, C., Burden, M. N., Kilpatrick, K. E., Morse, M. A., & Hamblin, P. A. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.11.5805 · Cited by 60
STAT5 Is Essential for Akt/p70S6 Kinase Activity during IL-2-Induced Lymphocyte Proliferation
Lockyer, H. M., Tran, E., & Nelson, B. H. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.8.5301 · Cited by 58 · cited 1×
“5 signaling (45) and thus can bypass the blockade of TCR ⁄ costimulatory-mediated Akt activation.”
Background
Turning on the off switch: Regulation of anti-viral T cell responses in the liver by the PD-1/PD-L1 pathway
Grakoui, A., Wherry, E. J., Hanson, H. L., Walker, C. M., & Ahmed, R. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2006.07.009 · Cited by 50
PD-1 deficiency reveals various tissue-specific autoimmunity by H-2 b and dose-dependent requirement of H-2 g7 for diabetes in NOD mice
Yoshida, T., Jiang, F., Honjo, T., & Okazaki, T. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710951105 · Cited by 49
Differential contribution of the immunoreceptor tyrosine-based inhibitory motifs of human leukocyte-associated Ig-like receptor-1 to inhibitory function and phosphatase recruitment
Verbrugge, A. (2003) · International Immunology · doi:10.1093/intimm/dxg134 · Cited by 47 · cited 14×
“Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation.”
BackgroundInfluential
Recruitment of C-terminal Src kinase by the leukocyte inhibitory receptor CD85j
Sayós, J., Martínez‐Barriocanal, Á., Kitzig, F., Bellón, T., & López‐Botet, M. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.09.097 · Cited by 45 · cited 14×
“Ship also binds to ITIMs and can inhibit PI3K activity (70).”
BackgroundInfluential
Dendritic Cells in Transplantation and Immune-Based Therapies
Young, J. W., Mérad, M., & Hart, D. N. J. (2007) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2006.10.023 · Cited by 34 · cited 1×
“In vivo, dendritic cells (DCs) are the best APCs for expansion of antigen-specific T cells (85).”
Background
Novel strategies to eliminate persistent viral infections
Martinic, M. M. A., & von Herrath, M. G. (2008) · Trends in Immunology · doi:10.1016/j.it.2007.12.002 · Cited by 32
The road to recovery: translating PD-1 biology into clinical benefit
Riley, J. L., & June, C. H. (2006) · Trends in Immunology · doi:10.1016/j.it.2006.12.001 · Cited by 30 · cited 1×
“those observed in human models (14), it would be interesting”
BackgroundSelf-citation
Regulation of cell signaling by the protein tyrosine phosphatases, CD45 and SHP-1
Ulyanova, T., Blasioli, J., & Thomas, M. L. (1997) · Immunologic Research · doi:10.1007/bf02786326 · Cited by 25 · cited 1×
“SHP-1 expression is largely confined to cells of hematopoietic lineage (53).”
Background
The interchain disulfide linkage is not a prerequisite but enhances CD28 costimulatory function
Lázár‐Molnár, E., Almo, S. C., & Nathenson, S. G. (2006) · Cellular Immunology · doi:10.1016/j.cellimm.2007.02.014 · Cited by 23 · cited 1×
“A monomeric version of CD28 bound CD80 less well and costimulated T cells less efficiently than the wildtype dimer, suggesting that the dimeric nature of CD28 contributes to its function (25).”
Background

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Background
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See all 781

Authors: Riley, J. L.
Affiliations: University of Pennsylvania (US)
Corresponding author: Riley, James L.
ORCID: Riley, James L.
Venue: Immunological Reviews
Publisher: Wiley
Published: 2009-04-21
Volume: 229
Issue: 1
Pages: 114-125
ISSN: 0105-2896 (ISSN-L)
1600-065X
DOI: 10.1111/j.1600-065x.2009.00767.x
PMC: PMC3424066
OpenAlex: W2017712207
Cited by: 778
References: 95
Citations by year: 2026: 21 · 2025: 39 · 2024: 37 · 2023: 66 · 2022: 73 · 2021: 84 · 2020: 64 · 2019: 61 · 2018: 60 · 2017: 49 · 2016: 33 · 2015: 41 · 2014: 34 · 2013: 37 · 2012: 30
FWCI: 2.32
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Immunological Reviews (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (CA113783, R01CA113783)
National Institute of Allergy and Infectious Diseases (AI080192, P01AI080192, R01AI057838, AI057838, PD-1 PO1AI080192)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords: PD-1 signaling, PDCD1, PD-L1, PD-L2, T cell exhaustion, T cell proliferation inhibition, cytotoxic T lymphocyte antigen 4, signal transduction, T cell differentiation, immune checkpoint, primary T cells
MeSH terms: Animals, Antigens, Surface, Humans, T-Lymphocytes, Signal Transduction, Antigens, CD, CD28 Antigens, Apoptosis Regulatory Proteins, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, CTLA-4 Antigen, Programmed Cell Death 1 Receptor

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PD-1 signaling in primary T cells

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