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

Mol Immunol. 2008 Jun;45(11):3074-84. doi: 10.1016/j.molimm.2008.03.019. Epub 2008 May 5.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CSK Tyrosine-Protein Kinase
  • Down-Regulation*
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Immunologic Memory
  • Jurkat Cells
  • Leukemia / enzymology
  • Leukemia / 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
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / metabolism*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology*
  • Transcriptional Activation
  • src-Family Kinases


  • 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