Colf Leremy A, Bankovich Alexander J, Hanick Nicole A, Bowerman Natalie A, Jones Lindsay L, Kranz David M, Garcia K Christopher
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell. 2007 Apr 6;129(1):135-46. doi: 10.1016/j.cell.2007.01.048.
alphabeta T cell receptors (TCRs) can crossreact with both self- and foreign- major histocompatibility complex (MHC) proteins in an enigmatic phenomenon termed alloreactivity. Here we present the 2.35 A structure of the 2C TCR complexed with its foreign ligand H-2L(d)-QL9. Surprisingly, we find that this TCR utilizes a different strategy to engage the foreign pMHC in comparison to the manner in which it recognizes a self ligand H-2K(b)-dEV8. 2C engages both shared and polymorphic residues on L(d) and K(b), as well as the unrelated QL9 and dEV8 peptide antigens, in unique pair-wise contacts, resulting in greater structural complementarity with the L(d)-QL9 complex. In the structure of an engineered, high-affinity 2C TCR variant bound to H-2L(d)-QL9, the "wild-type" TCR-MHC binding orientation persists despite modified TCR-CDR3alpha interactions with peptide. Thus, a single TCR recognizes two globally similar, but distinct ligands by divergent mechanisms, indicating that receptor-ligand crossreactivity can occur in the absence of molecular mimicry.
αβ T细胞受体（TCR）能与自身和外来的主要组织相容性复合体（MHC）蛋白发生交叉反应，这一神秘现象被称为同种异体反应性。在此，我们展示了与外来配体H-2L(d)-QL9复合的2C TCR的2.35 Å结构。令人惊讶的是，我们发现与识别自身配体H-2K(b)-dEV8的方式相比，该TCR采用了不同的策略来结合外来的肽-MHC复合物（pMHC）。2C通过独特的两两接触与L(d)和K(b)上的共有及多态性残基以及不相关的QL9和dEV8肽抗原相互作用，从而与L(d)-QL9复合物具有更大的结构互补性。在与H-2L(d)-QL9结合的工程化高亲和力2C TCR变体的结构中，尽管TCR互补决定区3α（CDR3α）与肽的相互作用发生了改变，但“野生型”TCR-MHC结合方向仍然存在。因此，单个TCR通过不同机制识别两种总体相似但又不同的配体，这表明在不存在分子模拟的情况下也会发生受体-配体交叉反应。
