TCR-induced downregulation of protein tyrosine phosphatase PEST augments secondary T cell responses.

Abstract

We report that the protein tyrosine phosphatase PTP-PEST is expressed in resting human and mouse CD4(+) and CD8(+) T cells, but not in Jurkat T leukemia cells, and that PTP-PEST protein, but not mRNA, was dramatically downregulated in CD4(+) and CD8(+) primary human T cells upon T cell activation. This was also true in mouse CD4(+) T cells, but less striking in mouse CD8(+) T cells. PTP-PEST reintroduced into Jurkat at levels similar to those in primary human T cells, was a potent inhibitor of TCR-induced transactivation of reporter genes driven by NFAT/AP-1 and NF-kappaB elements and by the entire IL-2 gene promoter. Introduction of PTP-PEST into previously activated primary human T cells also reduced subsequent IL-2 production by these cells in response to TCR and CD28 stimulation. The inhibitory effect of PTP-PEST was associated with dephosphorylation the Lck kinase at its activation loop site (Y394), reduced early TCR-induced tyrosine phosphorylation, reduced ZAP-70 phosphorylation and inhibition of MAP kinase activation. We propose that PTP-PEST tempers T cell activation by dephosphorylating TCR-proximal signaling molecules, such as Lck, and that down-regulation of PTP-PEST may be a reason for the increased response to TCR triggering of previously activated T cells.

• Authors: Yutaka Arimura, Torkel Vang, Lutz Tautz, Scott Williams, Tomas Mustelin
• Journal: Molecular immunology (Mol Immunol) Vol. 45 Issue 11 Pg. 3074-84 (Jun 2008) ISSN: 0161-5890 [Print] England
• PMID: 18457880 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Proto-Oncogene Proteins
• RNA, Messenger
• Receptors, Antigen, T-Cell
• Phosphotyrosine
• Protein-Tyrosine Kinases
• CSK Tyrosine-Protein Kinase
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
• src-Family Kinases
• CSK protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 12

Topics

• Animals
• CSK Tyrosine-Protein Kinase
• Down-Regulation
• Gene Expression Regulation, Enzymologic
• Humans
• Immunologic Memory
• Jurkat Cells
• Leukemia (enzymology, pathology)
• Lymphocyte Activation
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (metabolism)
• Membrane Microdomains (enzymology)
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Phosphotyrosine (metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 12 (genetics, metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptors, Antigen, T-Cell (immunology, metabolism)
• Signal Transduction
• T-Lymphocytes (enzymology, immunology)
• Transcriptional Activation
• src-Family Kinases