The Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Induce the Expression of Programmed Death-1 and Its Ligands
Open accessAbstract
The programmed death (PD)-1 molecule and its ligands (PD-L1 and PD-L2), negative regulatory members of the B7 family, play an important role in peripheral tolerance. Previous studies have demonstrated that PD-1 is up-regulated on T cells following TCR-mediated activation; however, little is known regarding PD-1 and Ag-independent, cytokine-induced T cell activation. The common gamma-chain (gamma c) cytokines IL-2, IL-7, IL-15, and IL-21, which play an important role in peripheral T cell expansion and survival, were found to up-regulate PD-1 and, with the exception of IL-21, PD-L1 on purified T cells in vitro. This effect was most prominent on memory T cells. Furthermore, these cytokines induced, indirectly, the expression of PD-L1 and PD-L2 on monocytes/macrophages in PBMC. The in vivo correlate of these observations was confirmed on PBMC isolated from HIV-infected individuals receiving IL-2 immunotherapy. Exposure of gamma c cytokine pretreated T cells to PD-1 ligand-IgG had no effect on STAT5 activation, T cell proliferation, or survival driven by gamma c cytokines. However, PD-1 ligand-IgG dramatically inhibited anti-CD3/CD28-driven proliferation and Lck activation. Furthermore, following restimulation with anti-CD3/CD28, cytokine secretion by both gamma c cytokine and anti-CD3/CD28 pretreated T cells was suppressed. These data suggest that gamma c cytokine-induced PD-1 does not interfere with cytokine-driven peripheral T cell expansion/survival, but may act to suppress certain effector functions of cytokine-stimulated cells upon TCR engagement, thereby minimizing immune-mediated damage to the host.
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Most circulating T cells do not express PD-1 but can be induced to do so upon stimulation through the TCR complex or cytokines such as IL-2, IL-7, IL-15, IL-21, and TGF-β.
“Although most circulating T cells do not express the receptor, they can be induced to do so upon stimulation, through the T cell receptor (TCR) complex or exposure to cytokines such as IL-2, IL-7, IL-15, IL-21, and transforming growth factor (TGF)-β (33, 34).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [34]
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- Authors
- Kinter, A. L., Godbout, E. J., McNally, J. P., Sereti, I., Roby, G. A., O’Shea, M. A., & Fauci, A. S.
- Affiliations
- National Institutes of Health (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-11
- Volume
- 181
- Issue
- 10
- Pages
- 6738-6746
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2158393416
- Cited by
- 513
- References
- 54
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 23 · 2023: 40 · 2022: 23 · 2021: 50 · 2020: 35 · 2019: 41 · 2018: 40 · 2017: 37 · 2016: 36 · 2015: 30 · 2014: 26 · 2013: 23 · 2012: 28
- FWCI
- 7.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- PDCD1, PD-L1, PD-L2, common gamma chain cytokines, interleukin-2, IL-7, IL-15, IL-21, T cell activation, memory T cells, monocytes/macrophages, people living with HIV, IL-2 immunotherapy, STAT5, Lck, T cell proliferation, T cell survival, peripheral tolerance, B7 family
- MeSH terms
- Interleukin-21, Cells, Cultured, Humans, Interleukin-2, Interleukins, Lymphocyte Activation, T-Lymphocytes, HIV Infections, Antigens, CD, Interleukin-7, Cytokines, Interleukin-15, Intercellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Programmed Cell Death 1 Ligand 2 Protein
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