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Role of the PD-1 Pathway in the Immune Response
Open accessAbstract
Understanding immunoregulatory mechanisms is essential for the development of novel interventions to improve long-term allograft survival. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, have emerged as critical inhibitory signaling pathways that regulate T cell response and maintain peripheral tolerance. PD-1 signaling inhibits alloreactive T cell activation, and can promote induced regulatory T cell development. Furthermore, the upregulation of PD-L1 on nonhematopoietic cells of the allograft may actively participate in the inhibition of immune responses and provide tissue-specific protection. In murine transplant models, this pathway has been shown to be critical for the induction and maintenance of graft tolerance. In this review, we discuss the current knowledge of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential in transplantation.
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“T cell proliferation and function can also be enhanced by blocking signalling through the inhibitory receptors such as PD-1 [77].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [77]
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“and this is an important strategic point because the use of PD-1/PD-L1 therapy has been reported to impair Treg cells in the renal allograft.173”
From Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy (2020) · cites this paper as [173]
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Cites
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“Another marker which was seen to be altered during chronic LE is programmed cell death protein 1 (PD-1); during inflammation, PD-1 plays an immunoregulatory role, acts as an immune barrier molecule to down-regulate T cell activities, and helps to control the T cell response and maintain peripheral tolerance [17,18,36,…”
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“Indeed, blockade of this pathway can rescue T cell effect or function and prevent apoptosis.(1-3) However, mechanisms by which PD-1 blockade restores T cell survival and functionality have not been precisely characterized.”
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“The binding of B7-H1 (programmed death-ligand 1) to its receptor, programmed cell death protein 1, can inhibit the proliferation of T cells and the secretion of some cytokines in vitro (29-31).”
REVIEW OF APPROACHES TO IMMUNOTHERAPY IN ONCOLOGY
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“receptor–mediated proliferation and cytokine production by CD4 T cells.(18,63,64) Also, the effect of PD-L2 in modulating asthma severity by inhibiting allergen-driven IL-12 production in DCs has been described.”
BackgroundPTEN Loss and PD-L1 Expression of Different Histological Patterns of Prostate Cancer
Kır, G., Cecikoğlu, G. E., Tarcan, Z. C., Kazan, H. Ö., & Yıldırım, A. (2021) · Pathology - Research and Practice · doi:10.1016/j.prp.2021.153738 · Cited by 5
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“In addition, several studies pointed out that CD103 and PD-1 expression was found on activated and antigenexperienced Tregs (Mouly et al., 2010; Riella et al., 2012; Sather et al., 2007; Suffia et al., 2005).”
BackgroundCurrent Landscape and Future Direction of PD-1/PD-L1 Checkpoint Inhibitors in Cancer Treatment
Serratì, S., & Margheri, F. (2023) · Biomolecules · doi:10.3390/biom13081209 · Cited by 5
“In particular, PD-1 plays a crucial inhibitory role in the signalling of programmed cell death in response to the T cell-mediated process [4].”
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“7-9 Blockade of the PD-1/PD-L1 pathway can activate immune responses and enhance anti-tumor effects.”
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Immunotherapy in liver transplantation for hepatocellular carcinoma: A comprehensive review
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“The PD-1/PD-L1 pathway is a key player in peripheral allograft tolerance [28, 29], and its blockade can lead to rejection through several potential mechanisms.”
Akbari, B., Hasan, M. M., & Islam, S. M. (2025) · Journal of drug targeting · doi:10.1080/1061186x.2025.2520306 · Cited by 4
“However, tumour cells exploit this regulatory mechanism by overexpressing PD-l1, allowing them to evade immune surveillance by suppressing t cell-mediated cytotoxicity [78,79].”
Update on mesenchymal stromal cell studies in organ transplant recipients
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“The PD-1/PD-L1 pathway is also involved in the maintenance of graft tolerance (14).”
BackgroundUtilisation concomitante du nivolumab et d’immunosuppresseurs chez un patient greffé rénal
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“The expression of immune checkpoint targets (PDL1-PD1, B7-CTLA4) [31,32] in MNG and GBM are different. qRT-PCR analysis revealed great variability of T-cell receptor PD1 expression in individual MNG cases (Figure 4A) were somewhat higher than PD1 expression in GBM (Figure 4A).”
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“This leads to metabolic reprogramming of T cells, inhibiting their activation and proliferation [33, 38].”
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“It mediates immune protection against cytotoxic T lymphocytes and modulates chronic immune responses, with its upregulation disrupting immune-protective pathways 16 .”
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“Moreover, data from some of the real-world studies suggest that anti-PD-1 seems to have a more pronounced rejection response, and therefore, anti-CTLA-4 immunotherapy is recommended as a treatment for patients from the perspective of transplant organ protection [23, 24].”
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“In recent years, the fi eld of cancer and treatment has made signi fi cant strides, primarily due to the introduction of high-throughput transcriptome sequencing technologies [8,9].”
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“While the CTLA-4 receptors inhibit T cell activation, mainly on the basis of competing for molecule CD80/CD86, the PD-1 receptor and its ligands constitute a separate signaling pathway (Riella et al., 2012).”
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“Tumor overexpress PD-L1 helps tumor survival by suppressing the immune system 40,41 .”
BackgroundRole of Regulatory T Lymphocytes in Health and Disease
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“PD-1 is an immunoregulatory protein present on immune cells that aids in the control of immunological reactions (8).”
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Aspari, M., Ong, V. H., Søndergaard, K. H., Næser, E. U., Hvid, M., Ravnskjær, K., Tam, A. Y. Y., Xu, S., Bian, X., Lopez, H., et al. (2026) · Annals of the Rheumatic Diseases · doi:10.1016/j.ard.2026.01.008 · Cited by 1
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Metadata
- Authors
- Riella, L. V., Paterson, A. M., Sharpe, A. H., & Chandraker, A.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Riella, L.V.
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 12
- Issue
- 10
- Pages
- 2575-2587
- ISSN
- 1600-6135 (ISSN-L)
- PMC
- PMC3784243
- OpenAlex
- W2144601357
- Cited by
- 444
- References
- 132
- Citations by year
- 2026: 25 · 2025: 25 · 2024: 39 · 2023: 35 · 2022: 33 · 2021: 40 · 2020: 38 · 2019: 36 · 2018: 42 · 2017: 50 · 2016: 25 · 2015: 22 · 2014: 21 · 2013: 13
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Institute of Allergy and Infectious Diseases (R01AI051559, P01 AI 56299, R01 AI-51559, P01AI056299)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- PD-1 pathway, PD-L1, PD-L2, allograft tolerance, immune regulation, regulatory T cells, peripheral tolerance, graft survival
- MeSH terms
- Graft Survival, Humans, Immune Tolerance, Lymphocyte Activation, Signal Transduction, Organ Transplantation, T-Lymphocytes, Regulatory, Programmed Cell Death 1 Receptor
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