Kinetics and Mechanics of Two-Dimensional Interactions between T Cell Receptors and Different Activating Ligands

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• 作者：Philippe Robert^&dagger ; ; ^&Dagger ; ; ^§ ; ; ^¶ ; ; Milos Aleksic^?/sup> ; Omer Dushek^?/sup> ; ^&dagger ; &dagger ; ; Vincenzo Cerundolo^&lowast ; &lowast ; ; Pierre Bongrand^&dagger ; ; ^&Dagger ; ; ^§ ; ; ^¶ ; ; ^{pierre.bongrand@inserm.fr} ; P.  ; Anton van  ; der  ; Merwe^?/sup> ; ^{anton.vandermerwe@path.ox.ac.uk}
• 刊名：Biophysical Journal
• 出版年：2012
• 出版时间：18 January 2012
• 年：2012
• 卷：102
• 期：2
• 页码：248-257
• 全文大小：494 K

文摘

Adaptive immune responses are driven by interactions between T?cell antigen receptors (TCRs) and complexes of peptide antigens (p) bound to Major Histocompatibility Complex proteins (MHC) on the surface of antigen-presenting cells. Many experiments support the hypothesis that T?cell response is quantitatively and qualitatively dependent on the so-called strength of TCR/pMHC association. Most available data are correlations between binding parameters measured in solution (three-dimensional) and pMHC activation potency, suggesting that full lymphocyte activation required a minimal lifetime for TCR/pMHC interaction. However, recent reports suggest important discrepancies between the binding properties of ligand-receptor couples measured in solution (three-dimensional) and those measured using surface-bound molecules (two-dimensional). Other reports suggest that bond mechanical strength may be important in addition to kinetic parameters. Here, we used a laminar flow chamber to monitor at the single molecule level the two-dimensional interaction between a recombinant human TCR and eight pMHCs with variable potency. We found that 1), two-dimensional dissociation rates were comparable to three-dimensional parameters previously obtained with the same molecules; 2), no significant correlation was found between association rates and activating potency of pMHCs; 3), bond mechanical strength was partly independent of bond lifetime; and?4), a suitable combination of bond lifetime and bond strength displayed optimal correlation with activation efficiency. These?results suggest possible refinements of contemporary models of signal generation by T?cell receptors. In conclusion, we reported, for the first time to our knowledge, the two-dimensional binding properties of eight TCR/pMHC couples in a cell-free system with single bond resolution.