General T-cell receptor antagonists to immunomodulate HLA-A2–restricted minor histocompatibility antigen HA-1–specific T-cell responses

Abstract

AbstractT-cell receptors (TCRs) of a series of minor histocompatibility antigen (mHag) HA-1–specific cytotoxic T-cell (CTL) clones isolated from 3 unrelated patients have been shown to use the same BV6S4A2 segment with conserved amino acids in the CDR3Vβ region. This suggests that different HA-1–specific TCRs interact similarly to the HA-1 antigen presented by the HLA-A2 molecule. The mHag HA-1 forms an immunogenic complex with HLA-A2 and induces strong alloimmune responses after stem cell transplantation (SCT). It was questioned, therefore, whether clonal and polyclonal HA-1–specific CTL responses can be antagonized by a single TCR antagonistic peptide. Functional analysis and molecular modeling of single and double amino acid substitutions of TCR contact residues, adjacent residues, and HLA-A2 binding residues resulted in 4 peptides with high affinity for HLA-A2 and with the capacity to inhibit the lysis of endogenously HA-1–expressing EBV-BLCL by 3 different HA-1–specific CTL clones. These peptides also efficiently antagonized HA-1–specific polyclonal CTL lines derived from 3 patients and significantly reduced the number of interferon-γ–producing HA-1–specific CTL of a patient with graft-versus-host disease after HA-1–mismatched SCT. These data show that general TCR antagonists can be developed that inhibit HLA-A2–restricted HA-1–specific CTL responses on the clonal and the polyclonal level and that TCR antagonists may modulate the immunodominant mHag HA-1 responses.