Piepenbrink Kurt H, Borbulevych Oleg Y, Sommese Ruth F, Clemens John, Armstrong Kathryn M, Desmond Clare, Do Priscilla, Baker Brian M
Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA.
Biochem J. 2009 Oct 12;423(3):353-61. doi: 10.1042/BJ20090732.
TCR (T-cell receptor) recognition of antigenic peptides bound and presented by MHC (major histocompatibility complex) molecules forms the basis of the cellular immune response to pathogens and cancer. TCRs bind peptide-MHC complexes weakly and with fast kinetics, features which have hindered detailed biophysical studies of these interactions. Modified peptides resulting in enhanced TCR binding could help overcome these challenges. Furthermore, there is considerable interest in using modified peptides with enhanced TCR binding as the basis for clinical vaccines. In the present study, we examined how fluorine substitutions in an antigenic peptide can selectively impact TCR recognition. Using a structure-guided design approach, we found that fluorination of the Tax peptide [HTLV (human T-cell lymphotropic virus)-1 Tax(11-19)] enhanced binding by the Tax-specific TCR A6, yet weakened binding by the Tax-specific TCR B7. The changes in affinity were consistent with crystallographic structures and fluorine chemistry, and with the A6 TCR independent of other substitutions in the interface. Peptide fluorination thus provides a means to selectively modulate TCR binding affinity without significantly perturbing peptide composition or structure. Lastly, we probed the mechanism of fluorine's effect on TCR binding and we conclude that our results were most consistent with a 'polar hydrophobicity' mechanism, rather than a purely hydrophobic- or electrostatic-based mechanism. This finding should have an impact on other attempts to alter molecular recognition with fluorine.
T细胞受体（TCR）识别由主要组织相容性复合体（MHC）分子结合并呈递的抗原肽，构成了针对病原体和癌症的细胞免疫反应的基础。TCR与肽-MHC复合物的结合较弱且动力学较快，这些特性阻碍了对这些相互作用的详细生物物理研究。能增强TCR结合的修饰肽有助于克服这些挑战。此外，人们对使用具有增强TCR结合能力的修饰肽作为临床疫苗的基础也有浓厚兴趣。在本研究中，我们研究了抗原肽中的氟取代如何选择性地影响TCR识别。采用结构导向设计方法，我们发现Tax肽[人类嗜T细胞病毒1型（HTLV-1）Tax(11-19)]的氟化增强了Tax特异性TCR A6的结合，但减弱了Tax特异性TCR B7的结合。亲和力的变化与晶体结构和氟化学一致，并且A6 TCR的变化与界面中的其他取代无关。因此，肽氟化提供了一种选择性调节TCR结合亲和力的方法，而不会显著干扰肽的组成或结构。最后，我们探究了氟对TCR结合作用的机制，得出的结论是，我们的结果与“极性疏水性”机制最为一致，而非纯粹基于疏水性或静电的机制。这一发现应该会对其他利用氟来改变分子识别的尝试产生影响。
