The spliceosomal phosphopeptide P140 controls the lupus disease by interacting with the HSC70 protein and via a mechanism mediated by gammadelta T cells.
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.
Page
Nicolas
N
CNRS UPR9021, Institut de biologie moléculaire et cellulaire, Strasbourg, France.
Schall
Nicolas
N
Strub
Jean-Marc
JM
Quinternet
Marc
M
Chaloin
Olivier
O
Décossas
Marion
M
Cung
Manh Thong
MT
Van Dorsselaer
Alain
A
Briand
Jean-Paul
JP
Muller
Sylviane
S
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism; D001665:Binding Sites; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008954:Models, Biological; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000276:immunology / Q000378:metabolism; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D050883:HSC70 Heat-Shock Proteins; D010446:Peptide Fragments; D016692:Receptors, Antigen, T-Cell, gamma-delta; D017412:Ribonucleoprotein, U1 Small Nuclear; C535176:spliceosomal peptide P140