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Potentiation of T Cell Stimulatory Activity by Chemical Fixation of a Weak Peptide-MHC Complex

  • Hwang, Inkyu (Department of Chemistry and Chemical Biology, The Scripps Research Institute) ;
  • Kim, Kwangmi (Department of Chemistry and Chemical Biology, The Scripps Research Institute) ;
  • Choi, Sojin (College of Pharmacy, Chungnam National University) ;
  • Lomunova, Maria (College of Pharmacy, Chungnam National University)
  • Received : 2016.09.08
  • Accepted : 2016.12.27
  • Published : 2017.01.31

Abstract

The stability of peptide-MHC complex (pMHC) is an important factor to shape the fate of peptide-specific T cell immune response, but how it influences on T cell activation process is poorly understood. To better understand that, we investigated various T cell activation events driven by $L^d$ MHCI loaded with graded concentrations of P2Ca and QL9 peptides, respectively, with 2C TCR Tg T cells; the binding strength of P2Ca for $L^d$ is measurably weaker than that of QL9, but either peptides in the context of $L^d$ interact with 2C TCR with a similar strength. When their concentrations required for early T cell activation events, which occur within several minutes to an hour, were concerned, $EC_{50}s$ of QL9 were about 100 folds lower than those of P2Ca, which was expected from their association constants for $L^d$. When $EC_{50}s$ for late activation events, which takes over several hours to occur, were concerned, the differences grew even larger (> 300 folds), suggesting that, due to weak binding, $L^d/P2Ca$ dissociate from each other more easily to lose its antigenicity in a short time. Accordingly, fixation of $L^d/P2Ca$ with paraformaldehyde resulted in a significant improvement in its immunogenicity. These results imply that binding strength of a peptide for a MHC is a critical factor to determine the duration of pMHC-mediated T cell activation and thus the attainment of productive T cell activation. It is also suggested that paraformaldehyde fixation should be an effective tool to ameliorate the immunogenicity of pMHC with a poor stability.

Keywords

chemical fixation;paraformaldehyde;peptide-MHC complex;T cell activation;T cell receptor

Acknowledgement

Supported by : CNU, National Research Foundation of Korea, Korea Food Research Institute

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