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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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“Like CTLA-4, PD-1 is induced upon effector T cell activation and is also highly expressed on Tregs [13–15].”
BackgroundTumor innervation: peripheral nerves take control of the tumor microenvironment
Gysler, S. M., & Drapkin, R. (2021) · Journal of Clinical Investigation · doi:10.1172/jci147276 · Cited by 230
“Likewise, cancer cells that express high levels of the PD-1 ligand PD-L1 escape immune surveillance through PD-1/ PD-L1–induced inhibition of PI3K/AKT signaling and suppressed T cell activation (60).”
BackgroundNeutrophils as potential therapeutic targets in hepatocellular carcinoma
Geh, D., Leslie, J., Rumney, R., Reeves, H. L., Bird, T. G., & Mann, D. A. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00568-5 · Cited by 223
Therapy for metastatic melanoma: the past, present, and future
Finn, L. E., Markovic, S. N., & Joseph, R. W. (2012) · BMC Medicine · doi:10.1186/1741-7015-10-23 · Cited by 224
“PD-L1 is a negative regulator of the immune system that acts through binding of the PD-1 present on activated lymphocytes and PD-L1/PD-1 interaction causes immune tolerance through apoptosis of the activated lymphocyte [66-68].”
BackgroundPatsoukis, N., Li, L., Sari, D., Petkova, V., & Boussiotis, V. A. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00319-13 · Cited by 187
“One of the critical signaling pathways targeted by PD-1 is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, by which PD-1 mediates inhibitory effects on T cell proliferation, cytokine production, and glucose uptake (2, 3).”
BackgroundBiochemical Signaling of PD-1 on T Cells and Its Functional Implications
Boussiotis, V. A., Chatterjee, P., & Li, L. (2014) · The Cancer Journal · doi:10.1097/ppo.0000000000000059 · Cited by 190
Dhupkar, P. M., Gordon, N. B., Stewart, J., & Kleinerman, E. S. (2018) · Cancer Medicine · doi:10.1002/cam4.1518 · Cited by 190
Clonal deletion and the fate of autoreactive thymocytes that survive negative selection
Pobezinsky, L. A., Angelov, G. S., Tai, X., Jeurling, S., Laethem, F. V., Feigenbaum, L., Park, J., & Singer, A. (2012) · Nature Immunology · doi:10.1038/ni.2292 · Cited by 183
Natarajan, A., Mayer, A. T., Xu, L., Reeves, R. E., Gano, J., & Gambhir, S. S. (2015) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.5b00318 · Cited by 169
Inhibitory Receptors on Lymphocytes: Insights from Infections
Odorizzi, P. M., & Wherry, E. J. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1100038 · Cited by 175
“This issue is especially important for those inhibitory receptors known to recruit SHP and SHIP molecules, because it has been proposed that baseline expression of these phosphatases can vary in different cell types and at different stages of immune responses (58, 71).”
BackgroundTargeting Glycosylated PD-1 Induces Potent Antitumor Immunity
Sun, L., Li, C.-W., Chung, E. M., Yang, R., Kim, Y., Park, A. H., Lai, Y., Yang, Y., Wang, Y.-H., Liu, J., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3133 · Cited by 167
“The inhibitory function of PD-l is primarily mediated by the tyrosine phosphatase SHP-2, which is recruited to the cytoplasmic domain of PD-1 and dephosphorylates the signaling molecules downstream of the TCR/CD28 (4, 5).”
BackgroundFisicaro, P., Barili, V., Rossi, M., Montali, I., Vecchi, A. L., Acerbi, G., Laccabue, D., Zecca, A., Penna, A., Missale, G., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00849 · Cited by 173
PD-1 and cancer: molecular mechanisms and polymorphisms
Salmaninejad, A., Khoramshahi, V., Azani, A., Soltaninejad, E., Aslani, S., Zamani, M. R., Zal, M., Nesaei, A., & Hosseini, S. M. (2017) · Immunogenetics · doi:10.1007/s00251-017-1015-5 · Cited by 165
“(Riley 2009).”
Myklebust, J. H., Irish, J. M., Brody, J., Czerwinski, D. K., Houot, R., Kohrt, H. E. K., Timmerman, J. M., SAID, J. W., Green, M. R., Delabie, J., et al. (2013) · Blood · doi:10.1182/blood-2012-04-421826 · Cited by 158
Immune suppression and reversal of the suppressive tumor microenvironment
Shimizu, K., Iyoda, T., Okada, M., Yamasaki, S., & Fujii, S. (2018) · International Immunology · doi:10.1093/intimm/dxy042 · Cited by 162
Bystander T cells in cancer immunology and therapy
Meier, S. L., Satpathy, A. T., & Wells, D. K. (2022) · Nature Cancer · doi:10.1038/s43018-022-00335-8 · Cited by 162
Celis-Gutierrez, J., Blattmann, P., Zhai, Y., Jarmuzynski, N., Ruminski, K., Grégoire, C., Ounoughene, Y., Fiore, F., Aebersold, R., Roncagalli, R., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.041 · Cited by 154
“The PD-1 and BTLA cytoplasmic segments possess a similar exon-intron organization that encodes a pair of immunoreceptor tyrosine-based motifs and differ from those of the CD28, CTLA4, and ICOS molecules (Figure S2A; Riley, 2009).”
BackgroundInfluentialBlocking TGF-β Signaling To Enhance The Efficacy Of Immune Checkpoint Inhibitor
Bai, X., Yi, M., Jiao, Y., Chu, Q., & Wu, K. (2019) · OncoTargets and Therapy · doi:10.2147/ott.s224013 · Cited by 153
“The tyrosine residues of ITIM and ITSM are phosphorylated and recruit SHP1/2, which could counteract the TCR/CD3- or CD28-mediated phosphorylation.(43) PD-1/PD-L1 signaling not only blocks TCR/CD3 pathway by dephosphorylating the core components of TCR Bai et al Dovepress”
BackgroundImmunosuppressive Effects of Multiple Myeloma Are Overcome by PD-L1 Blockade
Hallett, W. H. D., Jing, W., Drobyski, W. R., & Johnson, B. D. (2011) · Biology of Blood and Marrow Transplantation · doi:10.1016/j.bbmt.2011.03.011 · Cited by 152
“Engagement of PD-1 by its ligands, either PD-L1 (B7-H1, CD274) or PD-L2 (B7-DC, CD273), results in the activation of phosphatases that deactivate signals emanating from the T cell receptor [4].”
BackgroundHenson, S. M., Macaulay, R., Riddell, N. E., Nunn, C. J., & Akbar, A. N. (2015) · European Journal of Immunology · doi:10.1002/eji.201445312 · Cited by 146
Dose-Dependent Effect of Anti-CTLA-4 on Survival in Sepsis
Inoue, S., Bo, L., Bian, J., Unsinger, J., Chang, K. C., & Hotchkiss, R. S. (2011) · Shock · doi:10.1097/shk.0b013e3182168cce · Cited by 151
“Cytotoxic T-lymphocyte antigen 4 activates protein phosphatase 2A, which has an important role in regulation of phophatidylionositol-3 kinase signaling (28).”
BackgroundCD160 and PD-1 Co-Expression on HIV-Specific CD8 T Cells Defines a Subset with Advanced Dysfunction
Peretz, Y., He, Z., Shi, Y., Yassine‐Diab, B., Goulet, J.-P., Bordi, R., Filali‐Mouhim, A., Loubert, J.-B., Far, M. E., Dupuy, F. P., et al. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002840 · Cited by 150
“Previous studies have shown that CD160 and PD-1 interact with molecules downstream of the TCR [35,52].”
ResultInfluentialLi, Y., Li, F., Jiang, F., Lv, X., Zhang, R., Lü, A., & Zhang, G. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17071151 · Cited by 149
“After binding of PD-L1 or PD-L2, the recruitment of tyrosine phosphatases will begin and then generates an inhibitory signal blocking the downstream effects of PI3K/Akt pathway leading to cell cycle arrest and suppressed T-cell activation [10,25].”
BackgroundThe three main stumbling blocks for anticancer T cells
Baitsch, L., Marraco, S. A. F., Legat, A., Meyer, C., & Speiser, D. E. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.02.006 · Cited by 148
Moguche, A. O., Shafiani, S., Clemons, C., Larson, R. P., Dinh, C., Higdon, L. E., Cambier, C. J., Sissons, J. R., Gallegos, A. M., Fink, P. J., et al. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20141518 · Cited by 142
“PD-1 signaling can restrict T cell activation by inhibiting Akt activation; however, these studies were performed in CD8 T cells that did not express ICOS (Riley, 2009).”
BackgroundExhaustion of T lymphocytes in the tumor microenvironment: Significance and effective mechanisms
Gholami, M. D., Kardar, G. A., Saeedi, Y., Heidari, S., Garssen, J., & Falak, R. (2017) · Cellular Immunology · doi:10.1016/j.cellimm.2017.10.002 · Cited by 143
“Interestingly, CAR T cells, combined with PD1 blockade, strongly augmented anti-tumor responses [212], Laboratory results confirmed that inhibitory checkpoint pathways such as PD1 and CTLA-4 signaling can modify the metabolic programs of T cells [77,176].”
Khanam, A., Chua, J. V., & Kottilil, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115497 · Cited by 148
“PD-1 obstructs T cell receptor mediated signaling and induces functional exhaustion in T cells by inhibiting effector responses including cytokine production and cytolytic activities in CHB patients [37,67].”
BackgroundCurrent and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy
Makuku, R., Khalili, N., Razi, S., Keshavarz-Fathi, M., & Rezaei, N. (2021) · Journal of Immunology Research · doi:10.1155/2021/6661406 · Cited by 136
“This process eventually inhibits cytokine production, T cell proliferation, and survival through downregulating transcription of the prosurvival factor Bcl-XL [27, 30] (Figure 2).”
BackgroundRegulatory B cells in anti-tumor immunity
Zhang, Y., Gallastegui, N., & Rosenblatt, J. D. (2015) · International Immunology · doi:10.1093/intimm/dxv034 · Cited by 139
PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2
Xu, X., Hou, B., Fulzele, A., Masubuchi, T., Zhao, Y., Wu, Z., Hu, Y., Jiang, Y., Ma, Y., Wang, H., et al. (2020) · The Journal of Cell Biology · doi:10.1083/jcb.201905085 · Cited by 135
“…evolutionally and structurally related coinhibitory receptors that attenuate T cell activation (Carreno and Collins, 2003; Freeman et al., 2000; Nishimura and Honjo, 2001; Riley, 2009; Watanabe et al., 2003), acting as “checkpoints” to prevent overreactive T cells (Fuertes Marraco et al., 2015).”
BackgroundOrchestrating immune check-point blockade for cancer immunotherapy in combinations
Perez‐Gracia, J. L., Labiano, S., Rodriguez-Ruiz, M. E., Sanmamed, M. F., & Melero, I. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.01.002 · Cited by 131
“As a result, signaling events under the CD3-TCR complex and CD28 are deactivated [44,45 ,46,47].”
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“PD-L1 interaction with PD-1 on T cells leads not only to inhibition of proliferation but also to decreased IL-2 secretion by blocking downstream pathways of PI-3 kinase and Akt [45].”
BackgroundFunctional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells
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“Upon interaction with PD-L1, PD-1 counteracts signaling downstream of T cell receptor (TCR) ligation and CD28 co-stimulation (6).”
BackgroundDutta, S., Ganguly, A., Chatterjee, K., Spada, S., & Mukherjee, S. (2023) · Biology · doi:10.3390/biology12020218 · Cited by 137
“Several mutagenetic studies have shown that the inhibitory effect of PD-1 on T cells is mediated by activated ITSM [21].”
BackgroundPD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation
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“Interestingly, Akt has been shown to be hyper-phosphorylated in CD8 + T cells derived from SF (8), indicating that PD-1 signaling is not sufficient to downregulate the PI3K-Akt axis in these cells.”
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Blockade of the B7-H1/PD-1 pathway for cancer immunotherapy.
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Immune receptor inhibition through enforced phosphatase recruitment
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Immune Checkpoint Inhibition in Head and Neck Cancer
Forster, M. D., & Devlin, M.-J. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00310 · Cited by 123
“The inhibition of this interaction can enhance T-cell response and mediate clinical anti-tumor activity (20, 21).”
BackgroundTsutsumi, S., Saeki, H., Nakashima, Y., Ito, S., Oki, E., Morita, M., Oda, Y., Okano, S., & Maehara, Y. (2017) · Cancer Science · doi:10.1111/cas.13237 · Cited by 122
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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