Unpredicted phenotypes of two mutants of the TcR DMF5

Unpredicted phenotypes of two mutants of the TcR DMF5 When a T-cell Receptor (TcR) interacts with its cognate peptide-MHC (pMHC), it triggers activation of a signaling cascade that results in the elicitation of a T cell effector function. Different models have been proposed to understand which parameters are needed to obtain an optimal activation of the signaling. It was speculated that improving the binding of a TcR could bring a stronger pMHC recognition, hence a stronger stimulation of the T cell. However, it was recently shown that an increase in affinity does not seem to be sufficient to guarantee improved functionality. A combination of factors is necessary to place the modified TcR in an optimal functional window. We here compared the binding parameters of two mutants of the melanoma antigen peptide MART-127−35 specific TcR DMF5. The first mutant was previously isolated by others in a screen for improved TcR. It was reported to have an increased CD8-independent activity. We confirmed these data and showed that the enhancement was neither due to change in half life (t1/2) nor Kd of the pMHC-TcR complex. The second mutant was designed based on a previous report claiming that a particular polymorphic residue in the TRAV12-2 chain was stabilizing the TcR. We created a DMF5 mutant for this residue and showed that, unexpectedly, this TcR had acquired a reduced overall activity although the TcR-pMHC complex was more stable when compared to the TcR wild type complex (increased t1/2). In addition, the soluble TcR form of this mutant bound target cells less efficiently. From this we concluded that kinetic parameters do not always predict the superior functionality of mutant TcRs. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Immunological Methods Elsevier

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Publisher
Elsevier
Copyright
Copyright © 2015 Elsevier B.V.
ISSN
0022-1759
D.O.I.
10.1016/j.jim.2015.06.006
Publisher site
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Abstract

When a T-cell Receptor (TcR) interacts with its cognate peptide-MHC (pMHC), it triggers activation of a signaling cascade that results in the elicitation of a T cell effector function. Different models have been proposed to understand which parameters are needed to obtain an optimal activation of the signaling. It was speculated that improving the binding of a TcR could bring a stronger pMHC recognition, hence a stronger stimulation of the T cell. However, it was recently shown that an increase in affinity does not seem to be sufficient to guarantee improved functionality. A combination of factors is necessary to place the modified TcR in an optimal functional window. We here compared the binding parameters of two mutants of the melanoma antigen peptide MART-127−35 specific TcR DMF5. The first mutant was previously isolated by others in a screen for improved TcR. It was reported to have an increased CD8-independent activity. We confirmed these data and showed that the enhancement was neither due to change in half life (t1/2) nor Kd of the pMHC-TcR complex. The second mutant was designed based on a previous report claiming that a particular polymorphic residue in the TRAV12-2 chain was stabilizing the TcR. We created a DMF5 mutant for this residue and showed that, unexpectedly, this TcR had acquired a reduced overall activity although the TcR-pMHC complex was more stable when compared to the TcR wild type complex (increased t1/2). In addition, the soluble TcR form of this mutant bound target cells less efficiently. From this we concluded that kinetic parameters do not always predict the superior functionality of mutant TcRs.

Journal

Journal of Immunological MethodsElsevier

Published: Oct 1, 2015

References

  • Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies
    Aleksic, M.; Liddy, N.; Molloy, P.E.; Pumphrey, N.; Vuidepot, A.
  • Monoclonal TCR-redirected tumor cell killing
    Liddy, N.; Bossi, G.; Adams, K.J.; Lissina, A.; Mahon, T.M.
  • Engineering improved T cell receptors using an alanine-scan guided T cell display selection system
    Malecek, K.; Zhong, S.; McGary, K.; Yu, C.; Huang, K.
  • Soluble T cell receptors: novel immunotherapies
    Molloy, P.E.; Sewell, A.K.; Jakobsen, B.K.
  • T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity
    Stone, J.D.; Chervin, A.S.; Kranz, D.M.

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