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

Due to the central role of T cells in the pathogenesis of inflammatory diseases of the peripheral nervous system like the Guillain–Barre´ 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 Tcell receptor (TCR) cell signaling. Truncated peptides bound to MHC class II molecules and induced TCR internalization and expression of interferon g (IFN-g) and tumor necrosis factor a (TNF-a) 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 CD3q 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.