Abstract
While in many cases the half-life of T cell receptor (TCR) binding to a particular ligand is a good predictor of activation potential, numerous exceptions suggest that other physical parameter(s) must also play a role. Accordingly, we analyzed the thermodynamics of TCR binding to a series of peptide-MHC ligands, three of which are more stimulatory than their stability of binding would predict. Strikingly, we find that during TCR binding these outliers show anomalously large changes in heat capacity, an indicator of conformational change or flexibility in a binding interaction. By combining the values for heat capacity (ΔCp) and the half-life of TCR binding (t 1/2), we find that we can accurately predict the degree of T cell stimulation. Structural analysis shows significant changes in the central TCR contact residue of the peptide-MHC, indicating that structural rearrangements within the TCR-peptide-MHC interface can contribute to T cell activation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1367-1378 |
| Number of pages | 12 |
| Journal | Molecular cell |
| Volume | 12 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 2003 |
Funding
We thank L. Teyton for S2 cell lines expressing I-E k ; Brenda Smith for technical assistance; and A. Meibom, L. Wu, C. Sumen, N. Anikeeva, Y. Sykulev, and members of the Davis and Chien laboratory for helpful discussions. M.K. was a postdoctoral fellow of the Alfred Benzon Foundation and the Danish Medical Research Council, E.J.A. is a postdoctoral fellow of the Cancer Research Institute, and X.-l.H. is supported by the AHA and NIH. This work is supported by grants to K.C.G. from the NIH (AI418540) and the W.M. Keck Foundation and to M.M.D. from the NIH and from the Howard Hughes Medical Institute. We also thank Ms. Stephanie Wheaton for expert assistance in the preparation of the manuscript.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology