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Cited by 1,931T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersSignaling Pathways in Disease

CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms

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Parry, Richard V., Chemnitz, Jens M., Frauwirth, Kenneth A., Lanfranco, Anthony R., Braunstein, Inbal, Kobayashi, Sumire V., Linsley, Peter S., Thompson, Craig B. +1 more·2005·Molecular and Cellular Biology
DOI 10.1128/mcb.25.21.9543-9553.2005PMC PMC1265804
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Abstract

CTLA-4 and PD-1 are receptors that negatively regulate T-cell activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28-mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4-mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T-cell activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28-mediated activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/AKT activation was dependent upon the immunoreceptor tyrosine-based switch motif located in its cytoplasmic tail, adding further importance to this domain in mediating PD-1 signal transduction. Lastly, PD-1 ligation is more effective in suppressing CD3/CD28-induced changes in the T-cell transcriptional profile, suggesting that differential regulation of PI3K activation by PD-1 and CTLA-4 ligation results in distinct cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms.

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  • During chronic inflammation, T cells become exhausted and upregulate non-redundant inhibitory receptors such as PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT that limit their effectiveness.

    “During chronic inflammation in particular, T cells are known to become exhausted and to upregulate a wide range of non-redundant inhibitory receptors that limit their effectiveness, such as PD-1, CTLA-4, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), or T-Cell immunoreceptor with Ig And ITIM domains (TIGIT) [See Table 1 (9–11)].”

    From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [9]

  • Engagement of PD-1 causes tyrosine phosphorylation and an intracellular signaling cascade that mediates dephosphorylation of TCR proximal signaling components.

    “In these cells, engagement of PD-1 causes tyrosine residues to become phosphorylated, starting an intracellular signaling cascade that mediates the dephosphorylation of TCR proximal signaling components (9, 42–44).”

    From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [9]

  • CTLA-4 engagement with CD80/CD86 counteracts TCR-induced downstream signaling and suppresses the PI3K-Akt pathway via SHP-2 and PP2A.

    “On the other hand, CTLA-4 engagement with CD80/CD86 counteracts TCR-induced downstream signaling and suppresses PI3K-Akt pathway (vital signaling of T cell activation), via SHP-2 and protein phosphatase 2A (PP2A) [123, 124].”

    From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [123]

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Authors
Parry, R. V., Chemnitz, J. M., Frauwirth, K. A., Lanfranco, A. R., Braunstein, I., Kobayashi, S. V., Linsley, P. S., Thompson, C. B., & Riley, J. L.
Affiliations
  • University of Pennsylvania (US)
  • Rosetta Inpharmatics
Corresponding author
Riley, James L.
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2005-11-01
Volume
25
Issue
21
Pages
9543-9553
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.25.21.9543-9553.2005
PMC
PMC1265804
OpenAlex
W2140875987
Cited by
1,931
References
9
Citations by year
2026: 48 · 2025: 90 · 2024: 135 · 2023: 140 · 2022: 148 · 2021: 160 · 2020: 179 · 2019: 156 · 2018: 150 · 2017: 154 · 2016: 118 · 2015: 99 · 2014: 73 · 2013: 66 · 2012: 40
FWCI
7.80
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Allergy and Infectious Diseases (R01AI057838, AI057838)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
CTLA-4, PD-1, T cell activation, Akt phosphorylation, PI3K/Akt signaling, protein phosphatase 2A, okadaic acid, CD28, glucose metabolism, signal transduction, immune checkpoint receptors
MeSH terms
Phosphoinositide-3 Kinase Inhibitors, Antigens, Differentiation, Antigens, Surface, Enzyme Activation, Gene Expression Regulation, Humans, Lymphocyte Activation, Phosphatidylinositols, Phosphoprotein Phosphatases, Phosphorylation, T-Lymphocytes, Signal Transduction, Antigens, CD, CD3 Complex, CD28 Antigens, Okadaic Acid, Phosphatidylinositol 3-Kinases, Apoptosis Regulatory Proteins, Oncogene Protein v-akt, CTLA-4 Antigen, Programmed Cell Death 1 Receptor, In Vitro Techniques

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