General T-cell receptor antagonists to immunomodulate HLA-A2-restricted minor histocompatibility antigen HA-1-specific T-cell responses.
T-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 CDR3Vbeta 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-gamma-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.
den Haan
Joke M M
JM
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Mutis
Tuna
T
Blokland
Els
E
IJzerman
Ad P
AP
Goulmy
Els
E
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000494:pharmacology; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000276:immunology; D002460:Cell Line; D002999:Clone Cells / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000276:Adjuvants, Immunologic; C110615:HA-1 antigen; D015789:HLA-A2 Antigen; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell