CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development

Immunity. 2010 Mar 26;32(3):342-54. doi: 10.1016/j.immuni.2010.03.006.

Abstract

The kinase-phosphatase pair Csk and CD45 reciprocally regulate phosphorylation of the inhibitory tyrosine of the Src family kinases Lck and Fyn. T cell receptor (TCR) signaling and thymic development require CD45 expression but proceed constitutively in the absence of Csk. Here, we show that relative titration of CD45 and Csk expression reveals distinct regulation of basal and inducible TCR signaling during thymic development. Low CD45 expression is sufficient to rescue inducible TCR signaling and positive selection, whereas high expression is required to reconstitute basal TCR signaling and beta selection. CD45 has a dual positive and negative regulatory role during inducible but not basal TCR signaling. By contrast, Csk titration regulates basal but not inducible signaling. High physiologic expression of CD45 is thus required for two reasons-to downmodulate inducible TCR signaling during positive selection and to counteract Csk during basal TCR signaling.

Publication types

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

MeSH terms

  • Alleles
  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CSK Tyrosine-Protein Kinase
  • Cells, Cultured
  • Leukocyte Common Antigens / chemistry
  • Leukocyte Common Antigens / genetics
  • Leukocyte Common Antigens / immunology*
  • Leukocyte Common Antigens / metabolism
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphotyrosine / metabolism
  • Protein Binding
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / immunology*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-fyn / deficiency
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction*
  • Thymus Gland / growth & development
  • Thymus Gland / immunology*
  • Thymus Gland / metabolism
  • src-Family Kinases

Substances

  • Receptors, Antigen, T-Cell
  • Phosphotyrosine
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • Fyn protein, mouse
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Proto-Oncogene Proteins c-fyn
  • src-Family Kinases
  • Leukocyte Common Antigens
  • Ptprc protein, mouse