Cited by 465T-cell and B-cell ImmunologyProtein Tyrosine PhosphatasesImmune Response and Inflammation

TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways

Štefanová, Irena, Hemmer, Bernhard, Vergelli, Marco, Martin, Roland, Biddison, William E., Germain, Ronald N.·2003·Nature Immunology

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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Crossref · 10.1038/ni895

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63 of 63 references verified0 citation errors · 0 not checkable

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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
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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