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 Ser(140) were synthesized as potential candidates for the treatment of patients with lupus. Studies in the MRL/lpr and (NZB x NZW)F-1 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 Ser(140) 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.