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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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“Programmed death 1 (PD-1), an inhibitory costimulatory molecule, is induced on activated T cells, B cells, and NK cells, and plays a crucial role in regulating peripheral tolerance [6].”
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“The blockade of PD-1/PD-L1 or PD-1/PD-L2 interaction by PD-1 or PD-L1 inhibitors could restore T-cell or NK cell activation. the TCR-mediated signaling pathway, PD-1 prevents the activation of the pathway mediated by PI3K/Akt or Ras/MEK/Erk.”
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“CTLA-4 has been shown to interact with PP2A [55, 56], a negative regulator of Akt, mTOR, and MAPK signaling, while PD-1 can stimulate PTEN and SHP2 phosphatase activity, which negatively regulate PI3K signaling upstream of Akt [57].”
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BackgroundT-cell responses in hepatitis B and C virus infection: similarities and differences
Schmidt, J., Blum, H. E., & Thimme, R. (2013) · Emerging Microbes & Infections · doi:10.1038/emi.2013.14 · Cited by 82
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“Its inhibitory pathways have been proposed to be different from those of CTLA4 (9).”
Targeted Therapy and Immunosuppression in the Tumor Microenvironment
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“The strong overlap of TIGIT and PD-1 expands the results of earlier studies demonstrating the coexpression of both proteins [9, 13], but also other checkpoint receptors such as Lag3 [27] and Tim3 [28, 29], in tumour infiltrating lymphocytes and is consistent with recent reports describing comparable properties for the…”
ResultTumour PD-L1 Expression in Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis
Acheampong, E., Abed, A., Morici, M., Bowyer, S. E., Amanuel, B., Lin, W., Millward, M., & Gray, E. S. (2020) · Cells · doi:10.3390/cells9112393 · Cited by 78
Immune-Related Adverse Events: Pneumonitis
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From Microbiome to Inflammation: The Key Drivers of Cervical Cancer
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“Therefore, PD-1 mab drugs have been used clinically to specifically block the binding between PD-L1 and PD-1, reactivate the activity of T cells, and then kill tumor cells (Riley, 2009).”
BackgroundPD-1 expression conditions T cell avidity within an antigen-specific repertoire
Simon, S., Vignard, V., Florenceau, L., Dréno, B., Khammari, A., Lang, F., & Labarrière, N. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1104448 · Cited by 73
“Ligation of PD-1 with one of its ligands results in dampening early TCR signaling, through the recruitment of the phosphatases SHP-1 and SHP-2, leading to direct dephosphorylation of signaling intermediates.(3,7) Besides its role in maintenance of physiologic self-tolerance, PD-1 is also implicated in the downregulati…”
BackgroundTIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives
Yan, Z., Wang, C., Wu, J., Wang, J., & Ma, T. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00267-6 · Cited by 84
PD-1 coinhibitory signals: the link between pathogenesis and protection
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“As the effect of PD-1 triggering by PD-L1 or PD-L2 leads to blocking antigenspecific proliferation, cytokine production, cytolytic function, and pro-survival pathways this suggests that PD-1 could interfere with a very proximal step in T cell activation [78].”
BackgroundThe PD-1:PD-L1 axis in Inflammatory Arthritis
Canavan, M., Floudas, A., Veale, D. J., & Fearon, U. (2021) · BMC Rheumatology · doi:10.1186/s41927-020-00171-2 · Cited by 73
“receptor (TCR), is significantly upregulated [3, 4].”
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“grammed death ligand 2, negatively regulate T cell proliferation and cytokine production [28, 29].”
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“During antigen presentation PDL1-PD1 engage within the immunological synapse blocking T cell activation, proliferation and acquisition of effector capacities (16) by strongly inhibiting TCR signal transduction and CD28CD80 costimulation (17).”
BackgroundTsai, M., Chen, W., Lu, C., & Chen, M. (2019) · Oral Oncology · doi:10.1016/j.oraloncology.2019.02.027 · Cited by 71
Targeting Drp1 and mitochondrial fission for therapeutic immune modulation
Simula, L., Campanella, M., & Campello, S. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104317 · Cited by 66
“Unfortunately, it is still not known how mitochondria morphology is modulated in this scenario, but it has been reported that PD-1 modulates both mTOR and ERK (Extracellular-signal Regulated Kinase) pathways [98,99] and, as said, both of them are regulators of the Drp1-dependent mitochondrial fission [42,100].”
BackgroundHobo, W. A., Norde, W. J., Schaap, N. P., Fredrix, H., Maas, F., Schellens, K., Falkenburg, J. H. F., Korman, A. J., Olive, D., van der Voort, R., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102807 · Cited by 69
“Perhaps the impairment via these receptors depends more on the amount of signaling it has experienced than on the expression of the receptor as such, as has been suggested previously for PD-1 (17, 42).”
BackgroundWang, S., Li, H., Li, B., Xie, T., Zhu, T., Sun, L., Ren, H., & Ye, Z. (2016) · International Immunopharmacology · doi:10.1016/j.intimp.2016.05.016 · Cited by 67
Yu, L., Zhang, J., & Li, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.871076 · Cited by 68
REVIEW ARTICLE: B7 Family Molecules as Regulators of the Maternal Immune System in Pregnancy
Petroff, M. G., & Perchellet, A. (2010) · American Journal of Reproductive Immunology · doi:10.1111/j.1600-0897.2010.00841.x · Cited by 67
Melzer, M., Lopez-Martinez, A., & Altomonte, J. (2017) · Biomedicines · doi:10.3390/biomedicines5010008 · Cited by 71
“For example, PD-1 ligation on T cells leads to tolerance against antigens, inhibited activation, and susceptibility to apoptosis [23].”
BackgroundOsteoclast Immunosuppressive Effects in Multiple Myeloma: Role of Programmed Cell Death Ligand 1
Tai, Y., Cho, S., & Anderson, K. C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01822 · Cited by 68
T cell exhaustion and Interleukin 2 downregulation
Balkhi, M. Y., Ma, Q., Ahmad, S., & Junghans, R. P. (2014) · Cytokine · doi:10.1016/j.cyto.2014.11.024 · Cited by 70
“However, the activation of phosphatases such as SHP2 and PP2A have been reported and those are believed to generate inhibitory signals [98].”
BackgroundGaddis, D. E., Maynard, C. L., Weaver, C. T., Michalek, S. M., & Katz, J. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0512220 · Cited by 69
“Activation and proliferation of T cells can be controlled by accessory signaling molecules, some of which are inhibitory, such as PD-1 [54, 55].”
BackgroundFan, Z., Tian, Y., Chen, Z., Liu, L., Zhou, Q., He, J., Coleman, J., Dong, C., Li, N., Huang, J., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201911571 · Cited by 62
“Published under the terms of the CC BY 4.0 license EMBO Molecular Medicine e11571 | 2020 1 of 17 Signaling pathways leading from binding of PD-L1/2 to PD-1 down to inhibition of T-cell activation and cytokine expression have been relatively clear (Riley, 2009; Xia et al, 2016).”
BackgroundInfluentialDíaz-Tejedor, A., Lorenzo-Mohamed, M., Puig, N., García‐Sánz, R., Mateos, M., Garayoa, M., & Paíno, T. (2021) · Cancers · doi:10.3390/cancers13061353 · Cited by 66
Siglec‐5 is an inhibitory immune checkpoint molecule for human T cells
Vuchkovska, A., Glanville, D. G., Scurti, G. M., White, P., Nishimura, M. I., Ulijasz, A. T., & Iwashima, M. (2022) · Immunology · doi:10.1111/imm.13470 · Cited by 64
“Since ITIM and ITSM are both known to mediate the suppressive functions of PD-1 (21), we hypothesized that Siglec-5 also requires these motifs to suppress NFAT and AP-1.”
BackgroundInfluentialLu, B., Chen, L., Liu, L., Zhu, Y., Wu, C., Jiang, J., & Zhang, X. (2011) · Immunologic Research · doi:10.1007/s12026-011-8227-9 · Cited by 67
Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3
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Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma
Yang, W., & Lin, S.-F. (2015) · BioMed Research International · doi:10.1155/2015/341430 · Cited by 69
“Engagement of PD-1 by its ligands, PD-L1 (B7-H1, CD274) or PD-L2 (B7DC, CD273), results in the activation of phosphatases that deactivate signals emanating from the T-cell receptor [43].”
BackgroundSwanson, M. S., & Sinha, U. K. (2014) · Oral Oncology · doi:10.1016/j.oraloncology.2014.10.010 · Cited by 64
“This dephosphorylation results in depression of T cell proliferation, IL-2 release, and T cell survival [4].”
BackgroundImmune Checkpoint Therapy for Non-Small-Cell Lung Cancer: An Update
Xia, B., & Herbst, R. S. (2016) · Immunotherapy · doi:10.2217/imt.15.123 · Cited by 64
Waickman, A. T., & Powell, J. D. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103143 · Cited by 64
Dendritic cells in cancer immunotherapy: vaccines and combination immunotherapies
Kaliński, P., Muthuswamy, R., & Urban, J. A. (2013) · Expert Review of Vaccines · doi:10.1586/erv.13.22 · Cited by 67
“101 Riley JL. PD-1 signaling in primary T cells. Immunol. Rev. 229(1), 114–125 (2009).”
InfluentialPD-1/PD-L1 immune checkpoint inhibitors in advanced cervical cancer
Saglam, O., & Conejo-Garcia, J. R. (2018) · Integrative Cancer Science and Therapeutics · doi:10.15761/icst.1000272 · Cited by 64
“The PD-1/PD-L1 interactions leads to blockage of T cell activation by inhibiting TCR signal transduction and CD28-CD80 co-stimulation [18].”
BackgroundImmunometabolism: Another Road to Sepsis and Its Therapeutic Targeting
Kumar, V. (2018) · Inflammation · doi:10.1007/s10753-018-0939-8 · Cited by 66
“For example, this neutrophil PDL-1 upon engagement with PD-1 on the T cells can inhibit their stimulatory signaling event mediated by TCR signal transduction and CD28-co-stimulation even at very low levels of PD-1 [97, 98].”
BackgroundInfluentialTLR Stimulation during T-cell Activation Lowers PD-1 Expression on CD8+ T Cells
Zahm, C. D., Colluru, V. T., McIlwain, S. J., Ong, I. M., & McNeel, D. G. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0243 · Cited by 62
“In the case of PD-1, signalingmediatedbybinding to one of its ligands leads to reduced effector function (5).”
BackgroundElevated PD-L1 expression predicts poor survival outcomes in patients with cervical cancer
Gu, X., Dong, M., Liu, Z., Mi, Y., Yang, J., Zhang, Z., Liu, K., Jiang, L., Zhang, Y., Dong, S., et al. (2019) · Cancer Cell International · doi:10.1186/s12935-019-0861-7 · Cited by 61
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Life and Death Decision-Making by p53 and Implications for Cancer Immunotherapy
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“An effective adaptive immune response against tumor cells requires sufficiently activated CTLs that efficiently navigate to the tumor milieu, as well as adequate TAAs that are presented on MHC by APCs [79].”
BackgroundInfluentialTomé, M., Pappalardo, A., Soulet, F., López, J. J., Olaizola, J., Léger, Y., Dubreuil, M., Mouchard, A., Fessart, D., Delom, F., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0086 · Cited by 60
XIST and TSIX: Novel Cancer Immune Biomarkers in PD-L1-Overexpressing Breast Cancer Patients
Salama, E. A., Adbeltawab, R. E., & Tayebi, H. M. E. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01459 · Cited by 61
“This is maintained through PD-1 (expressed on T cells)/PD-L1 (expressed mainly in nonlymphoid organs) ligand binding leading to T-cell suppression (9).”
BackgroundImmune-Checkpoint Inhibitors in B-Cell Lymphoma
Armengol, M., Santos, J. C., Fernández-Serrano, M., Profitós-Pelejà, N., Ribeiro, M. L., & Roué, G. (2021) · Cancers · doi:10.3390/cancers13020214 · Cited by 61
Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors
Xu, X., Masubuchi, T., Cai, Q., Zhao, Y., & Hui, E. (2021) · eLife · doi:10.7554/elife.74276 · Cited by 59
“In both BTLA and PD-1, the ITIM tyrosine and ITSM 375 tyrosine are separated by 25 residues (Riley, 2009), and similar spacing are found in numerous 376 ITIM/ITSM-containing receptors (Supplementary File 4).”
Targeting monocytes/macrophages in fibrosis and cancer diseases: Therapeutic approaches
Conte, E. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108031 · Cited by 61
Targeting glycosylated antigens on cancer cells using siglec‐7/9‐based CAR T‐cells
Meril, S., Harush, O., Reboh, Y., Matikhina, T., Barliya, T., & Cohen, C. J. (2020) · Molecular Carcinogenesis · doi:10.1002/mc.23213 · Cited by 59
Our current understanding of checkpoint inhibitor therapy in cancer immunotherapy
Goleva, E., Lyubchenko, T. A., Kraehenbuehl, L., Lacouture, M. E., Leung, D. Y. M., & Kern, J. A. (2021) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2021.03.003 · Cited by 62
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Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia
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“, CD279, on immune cells and has been observed to alter many cytokines’ release/production both directly and indirectly through its downstream signaling via the phosphatases SHP-1/SHP-2 (23).”
BackgroundMechanisms of Indirect Acute Lung Injury
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“This causes the inhibition of downstream pathways through the dephosphorylation of proteins such as CD3 and ZAP70 (16, 25), preventing further T cell stimulation.”
BackgroundMcPherson, R. C., Konkel, J. E., Prendergast, C. T., Thomson, J. P., Ottaviano, R., Leech, M. D., Kay, O., Zandee, S., Sweenie, C. H., Wraith, D. C., et al. (2014) · eLife · doi:10.7554/elife.03416 · Cited by 61
“DOI: 10.7554/eLife.03416 8 of 20 Research article PIT drives demethylation of the Pdcd1 promoter PD-1 is rapidly upregulated by T cells upon initial TCR stimulation but is then lost over time (Riley, 2009).”
Influential
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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