Truncation of the neuritogenic peptide bP2(60–70) results in the generation of altered peptide ligands with the potential to interfere with T cell activation

Abstract

Due to the central role of T cells in the pathogenesis of inflammatory diseases of the peripheral nervous system like the Guillain–Barré syndrome, specific immunotherapies aim at modifying T cell responses. Use of truncated mutants of the neuritogenic peptide of myelin basic protein (MBP) has been shown to anergize autoreactive T cells and to reverse experimental autoimmune encephalitis (EAE). To establish a rationale basis for the use of altered peptide ligands (APLs) in the treatment of autoimmune diseases we designed a set of N- and C-terminally truncated mutants of the minimal experimental autoimmune neuritis (EAN) inducing bovine P2 (bP2) (60–70) peptide and compared them for the ability to induce immune responses and T cell receptor (TCR) cell signaling. Truncated peptides bound to MHC class II molecules and induced TCR internalization and expression of interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) with decreasing potency. None of the shortened mutants elicited a proliferative response in P2-specific T cells. Stimulation of these antigen-specific T cells with peptide bP2(62–69) using antigen presenting cells (APCs) prepulsed with bP2(60–70) resulted in a significant decrease of the proliferative response. In agreement with the observed effects on T cell activation, analysis of TCR signaling demonstrated a lack of CD3ε phosphorylation and MAPK activation. Moreover, repeated injection of bP2(62–69) significantly slowed progression of adoptive transfer EAN (AT-EAN). Taken together, these findings strongly suggest that peptide bP2(62–69) can favorably modulate the antigen-induced response of neuritogenic T cells.