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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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Items 201–300 of 781
Focus on PD-1/PD-L1 as a Therapeutic Target in Ovarian Cancer
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“Laboratory studies have provided evidence that inhibitory checkpoint pathways can alter the metabolic program of T cells (126, 188).”
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BackgroundInfluentialThe Immunopathology of Giant Cell Arteritis Across Disease Spectra
Robinette, M. L., Rao, D. A., & Monach, P. A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.623716 · Cited by 53
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Pavelescu, L. A., Enache, R. M., Roşu, O. A., Profir, M., Creţoiu, S. M., & Gașpar, B. S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179659 · Cited by 59
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Liang, H., Lu, Q., Yang, J., & Yu, G. (2023) · Research · doi:10.34133/research.0211 · Cited by 52
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Park, J., & Skålhegg, B. S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1680838 · Cited by 66
“Engagement of PD-1 by its ligands recruits SHP-1 and SHP-2 tyrosine phosphatases, which dephosphorylate downstream signaling molecules involved in the TCR and CD28 pathways (42, 43).”
Romano, S., Tufano, M., D’Arrigo, P., Vigorito, V., Russo, S., & Romano, M. F. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.08.015 · Cited by 51
“Interestingly, PD1 activation augmented p-70S6k levels in melanoma cells and enhanced tumor growth; in contrast, PD1 dampened mTOR signaling in T cells, which led to diminished T cell proliferation [114].”
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The double-edged sword: Harnessing PD-1 blockade in tumor and autoimmunity
Kuchroo, J. R., Hafler, D. A., Sharpe, A. H., & Lucca, L. E. (2021) · Science Immunology · doi:10.1126/sciimmunol.abf4034 · Cited by 51
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BackgroundCEACAM1 promotes CD8+ T cell responses and improves control of a chronic viral infection
Khairnar, V., Duhan, V., Patil, A., Zhou, F., Bhat, H., Thöns, C., Sharma, P., Adomati, T., Friendrich, S.-K., Bezgovsek, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04832-2 · Cited by 49
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“As PD-1 activity has been associated with impaired T cell function, we analyzed changes in PD-1 expression following BDL [10, 11, 23, 24].”
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Roper, E., Lum, T., Palme, C. E., Ashford, B., Ch’ng, S., Ranson, M., Boyer, M. J., Clark, J. R., & Gupta, R. (2017) · Pathology · doi:10.1016/j.pathol.2017.04.004 · Cited by 49
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“As the major immune checkpoint, PD-1 prevents autoimmunity, controls damage of the healthy tissues during infection, and promotes self-tolerance [20].”
BackgroundT cell immunotherapy enhanced by designer biomaterials
Dunn, Z. S., Mac, J., & Wang, P. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119265 · Cited by 48
“A recent study described the use of nanoparticles coated with two different antibodies that are specific for 4-1BB and PD-L1 (immunoswitches), resulting in T cell stimulation while simultaneously preventing PD-1-mediated T cell exhaustion.”
BackgroundSingle-cell profiling reveals periventricular CD56bright NK cell accumulation in multiple sclerosis
Rodríguez‐Lorenzo, S., van Olst, L., Rodriguez-Mogeda, C., Kamermans, A., van der Pol, S. M. A., Rodríguez, E., Kooij, G., & de Vries, H. E. (2022) · eLife · doi:10.7554/elife.73849 · Cited by 49
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“Anti-PD-1 Programmed death-1 (PD-1) is a negative regulator of the immune system that causes immune tolerance through apoptosis of the activated lymphocyte responsible for the evasion of melanoma cells [79, 80].”
TIGIT, A Novel Therapeutic Target for Tumor Immunotherapy
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BackgroundAtezolizumab for the treatment of non-small cell lung cancer
Santini, F. C., & Rudin, C. M. (2017) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1356717 · Cited by 47
“The extracellular component of PD-1 consists of a single domain resembling an immunoglobulin variable region (IgV), while the cytoplasmic component contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) followed by an immunoreceptor tyrosine-based switch motif (ITSM), which is required intact for PD-1 funct…”
BackgroundRegulation of GVHD and GVL Activity via PD-L1 Interaction With PD-1 and CD80
Cassady, K. M., Martin, P. J., & Zeng, D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03061 · Cited by 48
“The primary intracellular molecular mechanism responsible for PD-1 attenuation of the T cell response is attributed to the function of the immunoreceptor tyrosine-based inhibitory motif (ITIM) located in the cytoplasmic tail of PD-1 (7, 32).”
BackgroundThe IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension
Benson, L. N., Liu, Y., Wang, X., Xiong, Y., Rhee, S. W., Guo, Y., Deck, K. S., Mora, C. J., Li, L., Huang, L., et al. (2022) · Circulation Research · doi:10.1161/circresaha.121.320373 · Cited by 48
Haddad, A. F., Young, J. S., Gill, S. A., & Aghi, M. K. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.02.019 · Cited by 47
Regulation of post-translational modification of PD-L1 and advances in tumor immunotherapy
Feng, C., Zhang, L., Chang, X., Qin, D., & Zhang, T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1230135 · Cited by 46
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Synergy of Immune Checkpoint Blockade with a Novel Synthetic Consensus DNA Vaccine Targeting TERT
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The Impact of Malaria Parasites on Dendritic Cell–T Cell Interaction
Osii, R., Otto, T. D., Garside, P., Ndungu, F. M., & Brewer, J. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01597 · Cited by 49
Aberrant Glycosylation as Immune Therapeutic Targets for Solid Tumors
Matsumoto, Y., & Ju, T. (2023) · Cancers · doi:10.3390/cancers15143536 · Cited by 48
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“Several studies uncovered that PD-1 disrupts the activated signaling of TCR and costimulatory molecules (CD28), such as RAS/ERK, PI3K/AKT, and calcium-mediated signaling, thus curtailing the activation, proliferation, and cytokine production of activated T cells (65, 66).”
BackgroundThe Role of the CD28 Family Receptors in T-Cell Immunomodulation
Ciesielska-Figlon, K., & Lisowska, K. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021274 · Cited by 48
“Furthermore, unlike CTLA-4, PD-1 can hinder TCR-and CD28-triggered activation by enlisting inhibitory phosphatases like SHP-2, which dampens the initiation of PI3K activity [63].”
BackgroundRecovery from experimental autoimmune uveitis promotes induction of antiuveitic inducible Tregs
Lee, D. J., & Taylor, A. W. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.3a1014-466rr · Cited by 43
“The intracellular portion of PD-1 binds SHP-1 and -2 [26, 39, 40], which then target ZAP70 and PI3K [22, 41].”
BackgroundGoods, B. A., Hernandez, A., Lowther, D. E., Lucca, L. E., Lerner, B. A., Günel, M., Raddassi, K., Coric, V., Hafler, D. A., & Love, J. C. (2017) · PLoS ONE · doi:10.1371/journal.pone.0181538 · Cited by 43
“Increased IFNγ expression by PD-1CD4 T cells, coupled with an inability to recover proliferative capacity even in the presence of PD-1 blocking antibodies, suggests that these cells are terminally differentiated and resistant to entry into cell cycle, as has previously been described for CD8 T cells [25].”
MUC1 Mucin: A Putative Regulatory (Checkpoint) Molecule of T Cells
Agrawal, B., Gupta, N., & Konowalchuk, J. D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02391 · Cited by 44
Genotype Driven Therapy for Non-Small Cell Lung Cancer: Resistance, Pan Inhibitors and Immunotherapy
Singh, S. S., Dahal, A., Shrestha, L., & Jois, S. D. S. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867326666190222183219 · Cited by 42
Zhu, L., Sun, J., Wang, L., Li, Z., Wang, L., & Li, Z. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00962 · Cited by 43
“The interaction of PD-1/ PD-L1 can inhibit T-cell activation and proliferation, cytokine production, and cytolytic function (Riley, 2009).”
BackgroundRole of immune checkpoint inhibitors in the revolutionization of advanced melanoma care
Singh, S., Numan, A., Agrawal, N., Tambuwala, M. M., Singh, V., & Kesharwani, P. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106417 · Cited by 45
“PD-1 is a related inhibitory T cell receptor that, in contrast to CTLA-4, principally controls effector T cell response inside the peripheral tissues [31].”
BackgroundReversal of functional defects in highly differentiated young and old CD8 T cells by PDL blockade
Henson, S. M., Macaulay, R., Franzese, O., & Akbar, A. N. (2012) · Immunology · doi:10.1111/j.1365-2567.2011.03550.x · Cited by 42
Kim, M. J., & Ha, S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.767466 · Cited by 46
“Mechanistically, PD-1 suppresses various TCR downstream signaling pathways responsible for effector T cell function (e.g., AKT, PI3K, and mTOR) (Riley, 2009; Patsoukis et al., 2012; Pauken and Wherry, 2015; Sharpe and Pauken, 2018).”
BackgroundThe PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer
Henick, B. S., Herbst, R. S., & Goldberg, S. B. (2014) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.955794 · Cited by 41
“Recruiting SHP-2 produces an inhibitory signal, blocking downstream effects of PI3K and Akt [20], culminating in cell-cycle arrest and suppressed T-cell activation [21].”
BackgroundA novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis
Fallon, E. A., Girard, B., Chung, C., Lomas‐Neira, J., Heffernan, D. S., Monaghan, S. F., & Ayala, A. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.2mir0917-377r · Cited by 45
Álvarez‐González, C. A., Jones, M. B., Hambor, J., & Cobb, B. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.556813 · Cited by 42
“PSA-Associated Co-Regulatory Receptors Are IRGs The expression of PD-1 is strongly associated with suppression of the immune response, a phenomenon exploited by several cancers (40, 41).”
BackgroundPD-1/PD-L1 Axis as a Potential Therapeutic Target for Multiple Sclerosis: A T Cell Perspective
Li, H., Zheng, C., Han, J., Zhu, J., Liu, S., & Jin, T. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.716747 · Cited by 43
“Furthermore, the suppression of the inhibitory signal cascade generated by the binding of ITIM, ITSM, and SHP-1/2 to the PD1 cytoplasmic tail triggers chromatin changes in the promoter regions of the IL-2 and IFN-γ genes and upregulates their transcription (Riley, 2009).”
BackgroundDing, L., Zhang, X., Yu, P., Peng, F., Sun, Y., Wu, Y., Luo, Z., Li, H., Zeng, Y., Wu, M., et al. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.04.011 · Cited by 41
Salem, M. L. (2015) · World Journal of Hepatology · doi:10.4254/wjh.v7.i23.2449 · Cited by 42
Combination of targeted therapy and immunotherapy in melanoma
Blank, C. U., Hooijkaas, A. I., Haanen, J. B. A. G., & Schumacher, T. N. (2011) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-011-1079-2 · Cited by 43
“PD-1 signaling leads to a negative regulation of T cell activity, as demonstrated by a decreased TCR triggering–induced proliferation, cytokine production, and cytolytic activity [48].”
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Prajeeth, C. K., Jirmo, A. C., Krishnaswamy, J. K., Ebensen, T., Guzmán, C. A., Weiß, S., Constabel, H., Schmidt, R. E., & Behrens, G. M. N. (2010) · European Journal of Immunology · doi:10.1002/eji.200939790 · Cited by 42
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Davis, Z., Felices, M., Lenvik, T. R., Badal, S., Walker, J. T., Hinderlie, P., Riley, J. L., Vallera, D. A., Blazar, B. R., & Miller, J. S. (2021) · Blood Advances · doi:10.1182/bloodadvances.2019001110 · Cited by 40
“PD-1 (CD279) is a type I transmembrane receptor with an immunoglobulin (Ig)–like extracellular domain and a cytoplasmic tail containing an immunoreceptor tyrosine-based inhibitory motif.(3) PD-1 has been shown to suppress both the duration and intensity of the immune response to tumor cells, in part to limit damage to…”
BackgroundInfluentialSelf-citationDevelopment of CAR T Cell Therapy in Children—A Comprehensive Overview
Boettcher, M., Joechner, A., Li, Z., Yang, S. F., & Schlegel, P. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11082158 · Cited by 42
“However, the T cell receptors and immune checkpoint receptors are important homeostatic receptors involved in the physiological functions of T cells, for which further investigation to fully understand the impact of these modifications on co-signaling pathways is imperative in order to ensure patient safety, and to cr…”
BackgroundWang, Q., Bardhan, K., Boussiotis, V. A., & Patsoukis, N. (2021) · Advanced Biology · doi:10.1002/adbi.202100758 · Cited by 39
Outline of Salivary Gland Pathogenesis of Sjögren’s Syndrome and Current Therapeutic Approaches
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“These effects ultimately block T cell proliferation, diminish cytokine production and cytolytic function, and impair T cell survival (3, 42, 43).”
BackgroundTumor Targeted Nanocarriers for Immunotherapy
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“From the development of a tumoral microenvironment, which compromises DC maturation due to different reasons such as a hypoxic environment, high lactic acid concentration, and high expression of cytokines (IL-10) or factors (VEGF, TGF-β), to the upregulation of certain membrane proteins as PD-L1 that hamper the killin…”
BackgroundTargeting RNA N6-methyladenosine to synergize with immune checkpoint therapy
Zhou, X., Li, C., Chen, T., Li, W., Wang, X., & Yang, Q. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01746-6 · Cited by 38
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“Programmed death 1 (PD-1), a receptor expressed on the surface of T cells, is involved in inhibitory signal transmission [6, 7].”
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“PD-1 is an inhibitory receptor mainly expressed on activated, effector and so-called exhausted T cells (30).”
BackgroundThe Novel Diagnostic Techniques and Biomarkers of Canine Mammary Tumors
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“Expression of PD-1 is closely related to antigen exposure and T cell exhaustion in several infection systems (10, 24, 43), and we have previously shown that PD-1 is expressed more highly on dominant clonotypes within epitopespecific T cell populations (13).”
BackgroundNiu, B., Appleby, T. C., Wang, R., Morar, M., Voight, J., Villaseñor, A. G., Clancy, S., Wise, S. J., Belzile, J.-P., Papalia, G. A., et al. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b00822 · Cited by 37
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MethodImmunotherapies in chronic pain through modulation of neuroimmune interactions
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“Though this seems to stand in apparent contradiction to its potent inhibitory effect on T cell activation, it is assumed that PD-1 expression is increased upon activation as a feedback mechanism, in order to prevent overstimulation and autoimmunity [19].”
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“The interaction of programmed death (PD)-1 with PD-L1/2 forms such a coinhibitory pathway, and can inhibit proliferation, cytokine production, cytolytic function, and survival of T cells (6).”
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“In addition, programmed death-1 (PD-1) is another crucial inhibitor of T cell proliferation that diminishes the cytolytic functions of these cells (Riley 2009).”
BackgroundImmune checkpoint inhibitors in mCRPC - rationales, challenges and perspectives
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“Hence, the inflammatory response of the immune system is limited to a locally defined area, sparing the surrounding healthy tissue and averting generalized autoimmune responses.(20,21) However, by overexpressing PD-L1 and inducing PD-1 receptor expression on TILs and Tregs, certain tumors circumvent this specific immu…”
BackgroundRecent Advances in Monoclonal Antibody Therapy for Colorectal Cancers
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“ZAP70, PI3K/AKT, and RAS/MEK/ERK by recruitment of SHP phosphatase (50, 53, 126).”
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“PD-L1 engages PD-1 expressed on activated T cells, which transduces a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function [64].”
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“PD-1, also known as CD279, is a type I transmembrane protein with a molecular weight of 55 kDa from B7/CD28 family.(6,7) Inducible PD-1 expression has been seen on activated T (CD4þ and CD8þ), natural killer (NK), and B lymphocytes, as well as on activated monocytes, dendritic cells, and macrophages.”
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Two Cases of Primary Cutaneous Lymphoma With a γ/δ+ Phenotype and an Indolent Course
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A new molecular paradigm in mycosis fungoides and Sézary syndrome
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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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