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Selective Modulation of CD4⁺ T Cells from Lupus Patients by a Promiscuous, Protective Peptide Analog¹

Fanny Monneaux^*, Johan Hoebeke^*, Christelle Sordet, Céline Nonn, Jean-Paul Briand^*, Bernard Maillère, Jean Sibillia and Sylviane Muller^2,*

^* Centre National de la Recherche Scientifique (CNRS), Unité Propre de Recherche 9021, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France; Département de Rhumatologie, Hôpital de Hautepierre, Strasbourg, France; and Commissariat à l’Energie Atomique Saclay, Département d’Ingénierie et d’Etudes des Protéines, Gif-sur-Yvette, France

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.

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