The Spliceosomal Phosphopeptide P140 Controls the Lupus Disease by Interacting with the HSC70 Protein and via a Mechanism Mediated by γδ T Cells

• Published in: PloS one Vol. 4; no. 4; p. e5273
• Main Authors: Page, Nicolas, Schall, Nicolas, Strub, Jean-Marc, Quinternet, Marc, Chaloin, Olivier, Décossas, Marion, Cung, Manh Thong, Van Dorsselaer, Alain, Briand, Jean-Paul, Muller, Sylviane
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 23.04.2009
• Subjects: Apoptosis; Autoimmune diseases; Autoimmunity; Biochemistry/Biomacromolecule-Ligand Interactions; Biochemistry/Cell Signaling and Trafficking Structures; Biochemistry/Drug Discovery; CD4 antigen; CD8 antigen; Cell surface; Clinical trials; Disease control; Gene expression; HIV; Hsc70 protein; Human immunodeficiency virus; Immunology/Autoimmunity; Immunology/Immune Response; Immunology/Immunomodulation; Immunology/Innate Immunity; Localization; Lupus; Lymphocytes; Lymphocytes B; Lymphocytes T; Medical research; Mice; Microscopy; Monoclonal antibodies; NMR; Nuclear magnetic resonance; Peptides; Peripheral blood; Proteins; Rheumatology/Autoimmunity, Autoimmune, and Inflammatory Diseases; Rheumatology/Systemic Lupus Erythematosos; Ribonucleoproteins (small nuclear); Rodents; Spectrum analysis; Systemic lupus erythematosus; T cell receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005273

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 γδ 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.