T cell recognition and therapeutic effect of a phosphorylated synthetic peptide of the 70K snRNP protein administered in MRL/lpr mice

Abstract

Modifications of self antigens that occur during apoptosis might be involved in the generation of neo-antigens, which can break tolerance and induce autoimmunity. We have previously identifiedan epitope at residues 131–151 of the U1-70K snRNP protein, recognized by IgG antibodies and CD4⁺ T cells from at least two strains of lupus mice. With the aim of investigating the possible role of phosphorylation on the antigenicity of peptide 131–151 and to gain a better understanding of how this peptide can drive autoimmune response, we synthesized two peptides phosphorylated on Ser¹³⁷ and ¹⁴⁰, respectively. We show here that peptide P140 phosphorylated on Ser¹⁴⁰ is recognized by both CD4⁺ T cells and antibodies from MRL/lpr mice. Furthermore, intravenous administration to lupus-prone MRL/lpr mice of P140 in saline (but not of the non-phosphorylated peptide) decreased proteinuria and anti-DNA antibody production, and significantly prolonged survival of treated mice. We further demonstrated that P140 is recognized by antibodies from lupus patients and binds to various HLA DR molecules, offering new hope for manipulating T cell response in humans.