AN ALTERED PEPTIDE LIGAND ANTAGONIZES ANTIGEN-SPECIFIC CD8+ CTL IN PERIPHERAL BLOOD OF HAM/TSP PATIENTS

Abstract

P065 Human T lymphotropic virus type I (HTLV-I) associated myelopathy/ tropical spastic paraparesis (HAM/TSP) is an inflammatory neurologic disease associated with HTLV-I infection, in which chronically activated, HTLV-I-specific CD8+ cytotoxic T lymphocytes (CTLs) have been suggested to be immunopathogenic. In HLA-A2 HAM/TSP patients, CD8+ HTLV-I specific CTLs recognize an HTLV-I immunodominant peptide of the HTLV-I tax protein, tax 11-19. We examined the T-cell receptor (TCR) agonism/antagonism in HTLV-I tax 11-19-specific CTL in both cloned CTLs and bulk peripheral blood lymphocytes (PBL) from four HLA-A2 HAM/TSP patients using alanine substituted peptides at the TCR contact residues of the HTLV-I tax peptide. In CTL clones generated from PBL and cerebrospinal fluid of HLA-A2 HAM/TSP patients, an altered peptide ligand (APL) substituted at position five significantly decreased the CTL responses when compared to the native peptide. Moreover, this ligand were also shown to inhibit CTL responses to the native peptide in bulk PBL of HLA-A2 HAM/TSP patients. These data suggest that a modification of antigenic peptide at the central position can manipulate the T cell responses in bulk PBL from different individuals with an inflammatory disease, implying a potential immunotherapy using an APL in antigen-specific T-cell mediated diseases.