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

Nat Immunol. 2003 Mar;4(3):248-54. doi: 10.1038/ni895. Epub 2003 Feb 10.

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.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Feedback, Physiological / immunology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / immunology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / immunology*
  • Receptors, Antigen, T-Cell / antagonists & inhibitors
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / immunology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Receptors, Antigen, T-Cell
  • Mitogen-Activated Protein Kinases
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn6 protein, mouse