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PD-1 signaling in primary T cells
Open accessAbstract
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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“it is suggested that recruitment of SH2-domain containing protein tyrosine phosphatases (SHP-1 and/or SHP-2) to the immunoreceptor tyrosine-based switch motif (ITSM) within the PD-1 cytoplasmic tail inhibits signaling events, particularly PI3K/AKT activation, downstream signals of the T-cell receptor [34], and in turn results in T cell dysfunction.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [34]
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Cites
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PDL1 shapes the classical Hodgkin lymphoma microenvironment without inducing T-cell exhaustion
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“This is because PD-1 contains two tyrosine residues in its intracellular domain, which participate in the formation of theN-terminal immunoreceptor tyrosine-based inhibitorymotif (ITIM) and the C-terminal immunoreceptor tyrosine-based switch motif (ITSM).(143) The extracellular domain of PD-1 contains an IgV-like doma…”
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“As PD-1 is also well established to be a marker of activation on T cells 29,30 , our current finding suggests that the PD-1 + Tim-3 − TIGIT − T RM TIL population could be less exhaustive, and therefore more active and responsive in lung cancers.”
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“Environmental cues within an inflammatory lesion up-regulate expression of receptors on non-hematopoietic and non-lymphoidal cells such as epithelia that then engage with immune effector cells to suppress and eventually quell their activity (22, 23).”
BackgroundInvestigative drugs for the treatment of cutaneous T-cell lymphomas (CTCL): an update
Ramelyte, E., Dummer, R., & Guenova, E. (2019) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1654995 · Cited by 18
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“This increase could result in an auto-inhibition of Treg proliferation through a negative signal mediated by PD-1/PD-L1, disrupt immune tolerance, and ultimately promote HT (36).”
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“We assume that the inheritance of the PD-1 state x2 only depend on the PD-1 state y2 at the mother cells (Riley 2009), so that a2(y) = ν2φ2(y2), b2(y) = ν2(1 − φ2(y2)), where the conditional expectation φ2(y2) is assumed to increase with the PD-1 state y2 (Riley 2009) as follows: φ2(y2) = â2 + (…”
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McCarthy, D. P., Lofgren, M., Watt, A., Horton, H. M., Kieffer-Kwon, P., Ding, J. P., Kobold, S., Baeuerle, P. A., Hofmeister, R., Gutierrez, D. A., et al. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03556-7 · Cited by 17
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BackgroundDecreased Programmed Death-1 Expression on the T Cells of Patients With Ankylosing Spondylitis
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BackgroundMolecular Systems Architecture of Interactome in the Acute Myeloid Leukemia Microenvironment
Ayyadurai, V. A. S., Deonikar, P., McLure, K. G., & Sakamoto, K. M. (2022) · Cancers · doi:10.3390/cancers14030756 · Cited by 17
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BackgroundClinical Application of ImmunoPET Targeting Checkpoint Inhibitors
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“It belongs to the family of CD28/CTLA-4 immunoglobulin antibodies, whose expression is induced after activation in CD4+ and CD8+ T cells, B cells, and monocytes [21].”
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“There is mounting evidence that this is an incomplete picture of what occurs downstream of PD-1 ligation, perhaps shedding light on the incomplete and unexplained responsiveness to PD-1 blockade in the clinic (Riley, 2009; Wang et al., 2021).”
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BackgroundCutaneous CD56+ T-cell lymphoma developing during pembrolizumab treatment for metastatic melanoma
Zheng, Y. J., Lee, A., Pincus, L. B., Ho, W. W.-S., Vujic, M., & Ortiz‐Urda, S. (2018) · JAAD Case Reports · doi:10.1016/j.jdcr.2018.01.016 · Cited by 16
“Physiologically, strong PD-1 signaling inhibits T-cell proliferation, and a PD-1 blockade can increase immune function via an increase in T-cell proliferative capacity.(4) Hyperproliferation of T cells is associated with adverse events such as vitiligo,(2) sarcoidosis,(5) and autoimmune limbic encephalitis.”
BackgroundFrontiers and Opportunities: Highlights of the 2nd Annual Conference of the Chinese Antibody Society
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“Neutrophils suppress antitumoral immune responses [e.g., via programmed death-ligand 1 (PD-L1) expression], inhibit CD4 + and CD8 + T-cell proliferation, cytokine production, and cytotoxicity, and promote the expansion of regulatory (Treg) cells [180].”
Inhibitory immune checkpoints in cancer immunotherapy
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“PD-L1 plays a pivotal role in mediating the immune response against tumor cells through binding to the immune-inhibitory receptor known as programmed cell death protein 1 (PD-1), a member of the B7-CD28 gene superfamily.(8) PD-1 on immune cells binds to PD-L1 expressed on the surface of tumor cells, resulting in the i…”
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Guarnera, L., Bravo‐Pérez, C., & Visconte, V. (2023) · Bioengineering · doi:10.3390/bioengineering10101228 · Cited by 15
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Using Preclinical Data to Design Combination Clinical Trials of Radiation Therapy and Immunotherapy
Gough, M. J., Sharon, S., Crittenden, M. R., & Young, K. H. (2020) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2019.12.002 · Cited by 15
Sun, H. Y., Hartigan, C. R., Chen, C.-W., Sun, Y., Tariq, M., Robertson, J. M., Krummey, S. M., Mehta, A. K., & Ford, M. L. (2021) · American Journal of Transplantation · doi:10.1111/ajt.16571 · Cited by 17
Gatekeepers of intestinal inflammation
Arnett, H. A., & Viney, J. L. (2009) · Inflammation Research · doi:10.1007/s00011-009-0091-x · Cited by 15
CD8 T‐cell regulation by T regulatory cells and the programmed cell death protein 1 pathway
Penaloza‐MacMaster, P. (2017) · Immunology · doi:10.1111/imm.12739 · Cited by 15
Kamalinia, G., Engel, B. J., Srinivasamani, A., Grindel, B. J., Ong, J. N., Curran, M. A., Takahashi, T. T., Millward, S. W., & Roberts, R. W. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00264 · Cited by 15
T-regulatory cells infected with feline immunodeficiency virus up-regulate programmed death-1 (PD-1)
Achleitner, A., Clark, M. E., & Bienzle, D. (2011) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2011.06.009 · Cited by 15
Wang, X., Yang, X., Huang, C., Liu, T., Zang, H., Gu, Y., Zhang, Y., Zhu, X., Zhang, C., Guo, F., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217486 · Cited by 14
MicroRNAs in T Cell-Immunotherapy
Dosil, S. G., Rodríguez‐Galán, A., Sánchez‐Madrid, F., & Fernández‐Messina, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010250 · Cited by 16
Tohn, R., Blumenfeld, H., Haeryfar, S. M. M., Veerapen, N., Besra, G. S., Porcelli, S. A., & Delovitch, T. L. (2011) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2011.04323.x · Cited by 14
Vargas‐Inchaustegui, D. A., Xiao, P., Hogg, A. E., Demberg, T., McKinnon, K. M., Venzon, D. J., Brocca‐Cofano, E., DiPasquale, J., Lee, E. M., Hudacik, L., et al. (2013) · Virology · doi:10.1016/j.virol.2013.09.015 · Cited by 14
“Programmed death-1 (PD-1), an inhibitory surface co-receptor, is a member of the CD28/B7 family that is expressed on T cells, B cells and myeloid-derived cells (Riley, 2009; Ishida et al., 1992).”
BackgroundInduction of Follicular-Like CXCR5 + CD8 + T Cells by TGF- β 1/IL-23 Is Limited During HIV Infection
Perdomo-Celis, F., Feria, M. G., Taborda, N. A., & Rugeles, M. T. (2019) · Viral Immunology · doi:10.1089/vim.2019.0029 · Cited by 15
“…negative effect in the activation of T cells, and increased expression in CD8 + T cells from HIV-infected patients (57), PD-1 decreased the response of CD8 + T cells to TGF-b 1/IL-23, most likely due to the inhibition of the TCR signaling (49), an effect that was restored with receptor blockade.”
Multipotent mesenchymal stromal cells in kidney transplant recipients: The next big thing?
Sergeant, E., Buysse, M., Devos, T., & Sprangers, B. (2020) · Blood Reviews · doi:10.1016/j.blre.2020.100718 · Cited by 13
Liao, Z., Lv, X., Liu, S., He, Z., Chen, S., Wang, L., Li, W., & Li, Y. (2018) · Asia-Pacific Journal of Clinical Oncology · doi:10.1111/ajco.12850 · Cited by 14
METTL14 Enhances Antitumor Immunity through m6A-Dependent Loss of PD-1
Huang, C. C., Wang, X., Gu, Y., Ren, K., Zang, H., Zhang, Y., Pan, Y., Cheng, S., Zhu, X., Wu, S., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-25-0065 · Cited by 13
Sourcing cells for in vitro models of human vascular barriers of inflammation
McCloskey, M. C., Zhang, V. Z., Ahmad, S. D., Walker, S. N., Romanick, S., Awad, H. A., & McGrath, J. L. (2022) · Frontiers in Medical Technology · doi:10.3389/fmedt.2022.979768 · Cited by 13
Donini, C., Galvagno, F., Rotolo, R., Massa, A., Merlini, A., Scagliotti, G. V., Novello, S., Bironzo, P., Leuci, V., & Sangiolo, D. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02363-2 · Cited by 13
Afshari, A. R., Sanati, M., Ahmadi, S. S., Kesharwani, P., & Sahebkar, A. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216955 · Cited by 14
See, J.-X., Samudi, C., Abdulla, M. A., Vadivelu, J., & Shankar, E. M. (2017) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0005702 · Cited by 17
Role of PD-L1 Expression during the Progression of Submucosal Gastric Cancer
Ubukata, Y., Ogata, K., Sohda, M., Yokobori, T., Shimoda, Y., Handa, T., Nakazawa, N., Kimura, A., Kogure, N., Sano, A., et al. (2020) · Oncology · doi:10.1159/000509033 · Cited by 13
“PD-L1/2 is found on the surface of cancer cells that bind to the immune checkpoint receptor PD-1 on the surface of cytotoxic T cells, thereby inactivating active T cells and evading immune recognition [11-13].”
BackgroundNK cell dysfunction is linked with disease severity in SARS‐CoV‐2 patients
Asl, K. D., Mazloumi, Z., Majidi, G., Kalarestaghi, H., Sabetkam, S., & Rafat, A. (2022) · Cell Biochemistry and Function · doi:10.1002/cbf.3725 · Cited by 13
“PD‐1 (also called CD279) was initially detected on T, B, and myeloid cells.(69) Although there are conflicting reports about the PD‐1 expression in human and mouse NK cells,(70) PD‐1 expression were detected on healthy individuals NK cells in the recent years.”
BackgroundPeptide immunotherapy in experimental autoimmune encephalomyelitis
Anderton, S. M. (2015) · Biomedical Journal · doi:10.4103/2319-4170.158510 · Cited by 13
Grzywnowicz, M., & Giannopoulos, K. (2012) · Acta Haematologica Polonica · doi:10.1016/s0001-5814(12)32008-2 · Cited by 13
Spotlight on pembrolizumab in non-small cell lung cancer: the evidence to date
Chen, H., & Vachhani, P. J. (2016) · OncoTargets and Therapy · doi:10.2147/ott.s97746 · Cited by 13
“PD-1/PD-L1 pathway in oncology PD-1 is a type 1 transmembrane protein of the Ig superfamily that engages in inhibitory signal transmission.(25,26) Compared to CTLA-4, PD-1 is expressed more broadly and includes tumor-infiltrating lymphocytes (TIL; mainly CD4+ T-cells of which a large proportion are regulatory T-cells…”
Placenta immune infiltrates and perinatal outcomes
Ozen, M., Novak, C. M., & Burd, I. (2018) · American Journal of Reproductive Immunology · doi:10.1111/aji.12850 · Cited by 11
Dying cells expose a nuclear antigen cross-reacting with anti-PD-1 monoclonal antibodies
Metzger, P., Kirchleitner, S. V., König, L. M., Hörth, C., Kobold, S., Endres, S., Schnurr, M. M., & Duewell, P. (2018) · Scientific Reports · doi:10.1038/s41598-018-27125-6 · Cited by 13
Monoclonal antibodies for the treatment of non-hematological tumors: a safety review
Corsini, L. R., Fanale, D., Passiglia, F., Incorvaia, L., Gennusa, V., Bazan, V., & Russo, A. D. (2018) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2018.1550068 · Cited by 13
“noglobulin gene superfamily able to inhibit the activity of T cells [132].”
BackgroundCAR-T cells in solid tumors: engineering, biomarkers, translational pathways and the road ahead
Shaer, N. S. H. A., Masoud, I., Tleyjeh, A., Al-Attas, A. A., Al-Attas, M. A., Khan, M. I., & Yaqinuddin, A. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1796675 · Cited by 15
“This receptor accelerates exhaustion not only through direct interaction with PD-L1 on tumor cells, which can trigger apoptosis (88 – 91).”
PD-L1: Can it be a biomarker for the prognosis or a promising therapeutic target in cervical cancer?
Wang, R., Zhang, Y., & Shan, F. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108484 · Cited by 13
Svanberg, C., Nyström, S. N., Govender, M., Bhattacharya, P., Che, K. F., Ellegård, R., Shankar, E. M., & Larsson, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.790276 · Cited by 11
“Frontiers in Immunology 02 (PD-L) 1/PD-L2 (36), B7H3/B7H4 (37), HVEM (38), and/or galectin-9 (Gal-9) (39).”
White, D., Cote-Martin, A., Bleck, M., Garaffa, N., Shaaban, A., Wu, H. L., Liu, D., Young, D. S., Scheer, J. K., Lorenz, I. C., et al. (2023) · Molecular Immunology · doi:10.1016/j.molimm.2023.02.007 · Cited by 12
Kowalski, A., Malinowska, K., Olszewski, J., & Zielińska‐Bliźniewska, H. (2021) · Biomolecules · doi:10.3390/biom11070970 · Cited by 13
Costimulation in Lymphomas and Cancers
Mir, M. A. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-802585-7.00005-4 · Cited by 12
Bot, A. I., Qiu, Z., Wong, R. M. H., Obrocea, M., & Smith, K. A. (2010) · Journal of Translational Medicine · doi:10.1186/1479-5876-8-132 · Cited by 12
“Conversely, if the antigen exposure persists or elevates beyond a certain threshold, the specific T cells would undergo ‘exhaustion’ mediated primarily by PD-1, a quite distinctive mechanism of immune regulation [54,55].”
BackgroundBreast cancer vaccination: Latest advances with an analytical focus on clinical trials
Vajari, M. K., Sanaei, M., Salari, S., Rezvani, A., Ravari, M. S., & Bashash, D. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110696 · Cited by 10
Current progress in the development of therapeutic vaccines for chronic hepatitis B virus infection.
Ghasemi, F., Rostami, S., Ghayour‐Mobarhan, M., & Meshkat, Z. (2016) · PubMed Central · Cited by 11
Metabolic regulation of the HBV-specific T cell function
Barili, V., Boni, C., Rossi, M., Vecchi, A. L., Zecca, A., Penna, A., Missale, G., Ferrari, C. I., & Fisicaro, P. (2020) · Antiviral Research · doi:10.1016/j.antiviral.2020.104989 · Cited by 12
Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies
Hussain, K., Cragg, M. S., & Beers, S. A. (2021) · Cancers · doi:10.3390/cancers13194904 · Cited by 11
Nguyen, N. P., Ali, A., Vinh‐Hung, V., Gorobets, O., Chi, A., Mazibuko, T., Migliore, N., Vasileiou, M., Lehrman, D., Mohammadianpanah, Μ., et al. (2022) · Cancers · doi:10.3390/cancers15010244 · Cited by 13
“However, to avoid excessive damage to the normal organs, CD8 T cells also have PD-1 receptors which consist of 288 amino acid proteins and whose function is to attenuate the immune response [43].”
Background
Metadata
- 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
- 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
- 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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