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Cited by 614Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation

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Bardhan, Kankana, Anagnostou, Theodora, Boussiotis, Vassiliki A.·2016·Frontiers in Immunology
DOI 10.3389/fimmu.2016.00550PMC PMC5149523
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Abstract

The immune system has the difficult challenge of discerning and defending against a diversity of microbial pathogens, while simultaneously avoiding self-reactivity. T lymphocytes function as effectors and regulators of the immune system. While central tolerance mechanism results in deletion of the majority of self-reactive T lymphocytes during thymic selection, a fraction of self reactive lymphocytes escapes to the periphery and retains the potential to inflict destructive autoimmune pathology. The immune system evolved various mechanisms to restrain such auto-reactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (TRegs). These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programmed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC; CD273) plays a vital role in the induction and maintenance of peripheral tolerance and for the maintenance of T cell homeostasis. In contrast to its beneficial role in self-tolerance, the PD-1: PD-L1/L2 pathway mediates potent inhibitory signals that prevent the expansion and function of T effector cells and have detrimental effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events that are regulated by PD-1 triggering, and their consequences on the function of T effector cells.

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Crossref · 10.3389/fimmu.2016.00550

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Figures

Figure 1 Effect of PD-1 on major signaling pathways and subsequent metabolic reprograming in T cells. When T cell encounters a foreign antigen presented by MHC on the surface of APC, TCR gets phosphorylated upon oligomerization of TCR/CD3 chains, followed by recruitment of activated Lck and Zap-70 to the phosphorylated ITAM (tyrosine motifs) of TCR tail, leading to initiation of downstream TCR-signaling cascade. During TCR cross-linking, when PD-1 interacts with its ligands, the two tyrosine residues on PD-1 cytoplasmic tail also become phosphorylated, and SHP-2 is recruited to ITSM (also possibly SHP-1). As a consequence, Lck and Zap-70 become dephosphorylated. PD-1 ligation also causes inhibition of PI3K/Akt/mTOR and Ras/MAPK/Erk pathways, leading to downregulation of glycolysis and amino acid metabolism and increase in fatty acid oxidation in T cells. This alteration in T cell metabolic reprograming may change the course of T cell differentiation, leading to impaired differentiation of effector and memory T cells, while enhancing the differentiation of T regulatory cells and exhausted T cells.
Figure 1 Effect of PD-1 on major signaling pathways and subsequent metabolic reprograming in T cells. When T cell encounters a foreign antigen presented by MHC on the surface of APC, TCR gets phosphorylated upon oligomerization of TCR/CD3 chains, followed by recruitment of activated Lck and Zap-70 to the phosphorylated ITAM (tyrosine motifs) of TCR tail, leading to initiation of downstream TCR-signaling cascade. During TCR cross-linking, when PD-1 interacts with its ligands, the two tyrosine residues on PD-1 cytoplasmic tail also become phosphorylated, and SHP-2 is recruited to ITSM (also possibly SHP-1). As a consequence, Lck and Zap-70 become dephosphorylated. PD-1 ligation also causes inhibition of PI3K/Akt/mTOR and Ras/MAPK/Erk pathways, leading to downregulation of glycolysis and amino acid metabolism and increase in fatty acid oxidation in T cells. This alteration in T cell metabolic reprograming may change the course of T cell differentiation, leading to impaired differentiation of effector and memory T cells, while enhancing the differentiation of T regulatory cells and exhausted T cells.CC BY · PubMed Central
Figure 2 Biological and clinical implications of PD-1 ligation on T cell immune function. (A) Engagement of PD-1 by PD-L1 expressed on pathogen-presenting cells inhibits differentiation, activation, and expansion of pathogen-specific T cells in chronic infections. Therapeutic blockade of this pathway can improve pathogen-specific immunity. (B) Engagement of PD-1 by PD-L1 expressed on tissues and APC-presenting self-antigens prevents the generation of self-reactive T effector cells, promotes the differentiation of TReg cells, suppresses expansion of escaping self-reactive T cells, and prevents autoimmunity. Therapeutic activation of this pathway may promote transplantation tolerance and induce self-tolerance in autoimmune diseases. (C) Engagement of PD-1 by PD-L1 expressed on cancer cells and immune cells infiltrating the tumor microenvironment (TME) inhibits expansion of tumor-specific T cells, promotes the generation of TReg cells, promotes tumor tolerance, and suppresses antitumor immunity. Therapeutic blockade of this pathway can activate antitumor immune responses.
Figure 2 Biological and clinical implications of PD-1 ligation on T cell immune function. (A) Engagement of PD-1 by PD-L1 expressed on pathogen-presenting cells inhibits differentiation, activation, and expansion of pathogen-specific T cells in chronic infections. Therapeutic blockade of this pathway can improve pathogen-specific immunity. (B) Engagement of PD-1 by PD-L1 expressed on tissues and APC-presenting self-antigens prevents the generation of self-reactive T effector cells, promotes the differentiation of TReg cells, suppresses expansion of escaping self-reactive T cells, and prevents autoimmunity. Therapeutic activation of this pathway may promote transplantation tolerance and induce self-tolerance in autoimmune diseases. (C) Engagement of PD-1 by PD-L1 expressed on cancer cells and immune cells infiltrating the tumor microenvironment (TME) inhibits expansion of tumor-specific T cells, promotes the generation of TReg cells, promotes tumor tolerance, and suppresses antitumor immunity. Therapeutic blockade of this pathway can activate antitumor immune responses.CC BY · PubMed Central
Figure 3 PD-1/PD-L1 blockade enhances tumor rejection by activating T cells. (Left) When PD-1/PD-L1 pathway is active, promotes survival of cancer cells via antiapoptotic signals mediated via PD-L1 and inhibits signaling pathways that lead to activation and expansion of T cells that recognize tumor antigens. Together, these events lead to impaired generation of T effector and memory cells and preferentiation differentiation of TEX and TReg cells, which promote tumor tolerance. (Right) Blocking the PD-1/PD-L1 immune checkpoint pathway by anti-PD-1 or anti-PD-L1 antibodies suppresses cancer cell survival and enhances the antitumor responses of T cells, leading to tumor regression and rejection. In contrast to impaired TCR signaling induced by PD-1 engagement, PD-1/PD-L1 blockade causes activation of T cells by increasing PI3K/Akt or Ras/MAPK pathways, promoting differentiation of effector and memory T cells and suppression of TEX and TReg differentiation.
Figure 3 PD-1/PD-L1 blockade enhances tumor rejection by activating T cells. (Left) When PD-1/PD-L1 pathway is active, promotes survival of cancer cells via antiapoptotic signals mediated via PD-L1 and inhibits signaling pathways that lead to activation and expansion of T cells that recognize tumor antigens. Together, these events lead to impaired generation of T effector and memory cells and preferentiation differentiation of TEX and TReg cells, which promote tumor tolerance. (Right) Blocking the PD-1/PD-L1 immune checkpoint pathway by anti-PD-1 or anti-PD-L1 antibodies suppresses cancer cell survival and enhances the antitumor responses of T cells, leading to tumor regression and rejection. In contrast to impaired TCR signaling induced by PD-1 engagement, PD-1/PD-L1 blockade causes activation of T cells by increasing PI3K/Akt or Ras/MAPK pathways, promoting differentiation of effector and memory T cells and suppression of TEX and TReg differentiation.CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Carter, 2002, PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2, Eur J Immunol, 32, 634, 10.1002/1521-4141(200203)32:3634::AID-IMMU6343.0.CO;2-9 · DOI

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Metadata

Authors
Bardhan, K., Anagnostou, T., & Boussiotis, V. A.
Affiliations
  • Beth Israel Deaconess Medical Center (US)
  • Mayo Clinic (US)
Corresponding author
Boussiotis, Vassiliki A.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2016-12-12
Volume
7
Pages
550-550
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2016.00550
PMC
PMC5149523
OpenAlex
W2560827811
Cited by
606
References
210
Citations by year
2026: 38 · 2025: 53 · 2024: 83 · 2023: 60 · 2022: 63 · 2021: 100 · 2020: 69 · 2019: 74 · 2018: 45 · 2017: 20
FWCI
4.66
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Foundation for the National Institutes of Health (CA183605, CA183605S1, AI098129-01)
  • U.S. Department of Defense (PC140571)
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 › Immunotherapy and Immune Responses
Keywords
PD-1, PD-L1, PD-L2, immune checkpoint, T cell tolerance, peripheral tolerance, T cell homeostasis, T cell anergy, regulatory T cells, antitumor immunity, antiviral immunity, immune checkpoint blockade, T cell signaling

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