SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation
Abstract
To study the cis- and trans-acting factors that mediate programmed death 1 (PD-1) signaling in primary human CD4 T cells, we constructed a chimeric molecule consisting of the murine CD28 extracellular domain and human PD-1 cytoplasmic tail. When introduced into CD4 T cells, this construct mimics the activity of endogenous PD-1 in terms of its ability to suppress T cell expansion and cytokine production. The cytoplasmic tail of PD-1 contains two structural motifs, an ITIM and an immunoreceptor tyrosine-based switch motif (ITSM). Mutation of the ITIM had little effect on PD-1 signaling or functional activity. In contrast, mutation of the ITSM abrogated the ability of PD-1 to block cytokine synthesis and to limit T cell expansion. Further biochemical analyses revealed that the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.
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“Additionally, it may assist in promoting cancer cell apoptosis and the proliferation of antigen-specific T cells, while simultaneously inducing apoptosis in T-regulatory cells [38].”
Background
- Authors
- Chemnitz, J. M., Parry, R. V., Nichols, K. E., June, C. H., & Riley, J. L.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-07
- Volume
- 173
- Issue
- 2
- Pages
- 945-954
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2130506153
- Cited by
- 1,246
- References
- 3
- Citations by year
- 2026: 43 · 2025: 52 · 2024: 68 · 2023: 92 · 2022: 89 · 2021: 106 · 2020: 107 · 2019: 72 · 2018: 75 · 2017: 96 · 2016: 66 · 2015: 75 · 2014: 51 · 2013: 41 · 2012: 26
- FWCI
- 7.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI057838, AI057838)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- PD-1, SHP-1, SHP2, ITIM, CD4+ T cells, T cell activation, T cell suppression, receptor ligation, T cell receptor signaling, cytokine production
- MeSH terms
- Antigens, Surface, Humans, Receptors, Immunologic, Recombinant Fusion Proteins, T-Lymphocytes, Tyrosine, Antigens, CD, Protein Tyrosine Phosphatases, Apoptosis, CD28 Antigens, Intracellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Phosphatase 1, Programmed Cell Death 1 Receptor
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