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General T-cell receptor antagonists to immunomodulate HLA-A2-restricted minor histocompatibility antigen
Joke M M den Haan1, Tuna Mutis, Els Blokland
1Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
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.
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.