A discrete affinity-driven elevation of ZAP-70 kinase activity initiates negative selection

J Recept Signal Transduct Res. 2010 Dec;30(6):430-43. doi: 10.3109/10799893.2010.518151. Epub 2010 Oct 14.

Abstract

Context: Although ZAP-70 is required for T-cell development, it's unclear how this kinase controls both positive and negative selection.

Objective and methods: Using OT-I pre-selection thymocytes and a panel of peptide major histocompatibility complex (pMHC) ligands of defined affinity, the recruitment, phosphorylation and activity of ZAP-70 was determined at the interface with antigen-presenting cells (APCs).

Results: pMHC ligands promoting negative selection induce a discrete elevation of ZAP-70 recruitment, phosphorylation and enzymatic activity in the thymocyte:APCs interface.

Discussion: The quantity of ZAP-70 kinase activity per cell is a key parameter controlling the fate of a developing thymocyte since partial inhibition of ZAP-70 kinase activity converted negative into positive selection. Surprisingly, the amount of ZAP-70 enzymatic activity observed during negative selection is not controlled by differential phosphorylation of the ZAP-70 protein but rather by the total amount of T-cell receptor and co-associated ZAP-70 recruited to the thymocyte:APC interface.

Conclusions: These data provide evidence that a burst of ZAP-70 activity initiates the signaling pathways for negative selection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Ligands
  • Lymphocyte Activation / immunology*
  • Major Histocompatibility Complex
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / physiology
  • ZAP-70 Protein-Tyrosine Kinase / genetics
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*

Substances

  • Ligands
  • Receptors, Antigen, T-Cell
  • ZAP-70 Protein-Tyrosine Kinase