The spliceosomal phosphopeptide P140 controls the lupus disease by interacting with the HSC70 protein and via a mechanism mediated by gammadelta T cells

PLoS One. 2009;4(4):e5273. doi: 10.1371/journal.pone.0005273. Epub 2009 Apr 23.


The phosphopeptide P140 issued from the spliceosomal U1-70K snRNP protein is recognized by lupus CD4(+) T cells, transiently abolishes T cell reactivity to other spliceosomal peptides in P140-treated MRL/lpr mice, and ameliorates their clinical features. P140 modulates lupus patients' T cell response ex vivo and is currently included in phase IIb clinical trials. Its underlying mechanism of action remains elusive. Here we show that P140 peptide binds a unique cell-surface receptor, the constitutively-expressed chaperone HSC70 protein, known as a presenting-protein. P140 induces apoptosis of activated MRL/lpr CD4(+) T cells. In P140-treated mice, it increases peripheral blood lymphocyte apoptosis and decreases B cell, activated T cell, and CD4(-)CD8(-)B220(+) T cell counts via a specific mechanism strictly depending on gammadelta T cells. Expression of inflammation-linked genes is rapidly regulated in CD4(+) T cells. This work led us to identify a powerful pathway taken by a newly-designed therapeutic peptide to immunomodulate lupus autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • B-Lymphocytes / metabolism
  • Binding Sites
  • Down-Regulation
  • Fluorescent Antibody Technique
  • HSC70 Heat-Shock Proteins / metabolism*
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / therapy
  • Mice
  • Mice, Inbred MRL lpr
  • Models, Biological
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Receptors, Antigen, T-Cell, gamma-delta / analysis
  • Ribonucleoprotein, U1 Small Nuclear / immunology
  • Ribonucleoprotein, U1 Small Nuclear / metabolism
  • Surface Plasmon Resonance
  • T-Lymphocytes / immunology
  • T-Lymphocytes, Regulatory / immunology*


  • HSC70 Heat-Shock Proteins
  • Peptide Fragments
  • Receptors, Antigen, T-Cell, gamma-delta
  • Ribonucleoprotein, U1 Small Nuclear
  • spliceosomal peptide P140