Selective modulation of CD4+ T cells from lupus patients by a promiscuous, protective peptide analog.
A peptide encompassing residues 131-151 of the spliceosomal U1-70K protein and its analog phosphorylated at Ser140 were synthesized as potential candidates for the treatment of patients with lupus. Studies in the MRL/lpr and (NZB x NZW)F1 lupus models have demonstrated that these sequences contain a CD4+ T cell epitope but administration of the phosphorylated peptide only ameliorates the clinical manifestations of treated MRL/lpr mice. Binding assays with soluble HLA class II molecules and molecular modeling experiments indicate that both peptides behave as promiscuous epitopes and bind to a large panel of human DR molecules. In contrast to normal T cells and T cells from non-lupus autoimmune patients, we found that PBMCs from 40% of lupus patients selected randomly and CFSE-labeled CD4+ T cells proliferate in response to peptide 131-151. Remarkably, however, we observed that phosphorylation of Ser140 prevents CD4+ T cells proliferation but not secretion of regulatory cytokines, suggesting a striking immunomodulatory effect of phosphorylated analog on lupus CD4+ T cells that was unique to patients. The analog might act as an activator of regulatory T cells or as a partial agonist of TCR.
Monneaux
Fanny
F
Centre National de la Recherche Scientifique (CNRS), Unité Propre de Recherche 9021, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
Hoebeke
Johan
J
Sordet
Christelle
C
Nonn
Céline
C
Briand
Jean-Paul
JP
Maillère
Bernard
B
Sibillia
Jean
J
Muller
Sylviane
S
D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000494:pharmacology*
D006684:HLA-DR Antigens; D010446:Peptide Fragments; D017412:Ribonucleoprotein, U1 Small Nuclear; C490688:SNRNP70 protein, human; D016753:Interleukin-10