TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways
Abstract
Functional discrimination between structurally similar self and foreign antigens is a main attribute of adaptive immunity. Here we describe two feedback mechanisms in T lymphocytes that together sharpen and amplify initial signaling differences related to the quality of T cell receptor (TCR) engagement. Weakly binding ligands predominantly trigger a negative feedback loop leading to rapid recruitment of the tyrosine phosphatase SHP-1, followed by receptor desensitization through inactivation of Lck kinase. In contrast, strongly binding ligands efficiently activate a positive feedback circuit involving Lck modification by ERK, preventing SHP-1 recruitment and allowing the long-lasting signaling necessary for gene activation. The characteristics of these pathways suggest that they constitute an important part of the mechanism allowing T cells to discriminate between self and foreign ligands.
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DUSP6 dephosphorylates ERK, attenuating ERK signaling after TCR activation and interfering with a forward feedback loop in TCR signaling.
“DUSP6 dephosphorylates ERK, not only attenuating ERK signaling after TCR activation but also interfering with a forward feedback loop in TCR signaling”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Stefanová et al., 2003
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- Authors
- Štefanová, I., Hemmer, B., Vergelli, M., Martin, R., Biddison, W. E., & Germain, R. N.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Germain, Ronald N.
- Venue
- Nature Immunology
- Published
- 2003-02-10
- Volume
- 4
- Issue
- 3
- Pages
- 248-254
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W1971692004
- Cited by
- 465
- References
- 63
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 15 · 2023: 13 · 2022: 14 · 2021: 19 · 2020: 19 · 2019: 19 · 2018: 11 · 2017: 16 · 2016: 17 · 2015: 14 · 2014: 28 · 2013: 24 · 2012: 28
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- T cell receptor signaling, ligand discrimination, Lck kinase, receptor desensitization, T cell activation, protein tyrosine phosphatase, signal amplification
- MeSH terms
- Animals, Humans, Ligands, Mice, Transgenic, Receptors, Antigen, T-Cell, Signal Transduction, Protein Tyrosine Phosphatases, CD8-Positive T-Lymphocytes, Mitogen-Activated Protein Kinases, Feedback, Physiological, Intracellular Signaling Peptides and Proteins, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 6
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