TY - JOUR
T1 - How a Single T Cell Receptor Recognizes Both Self and Foreign MHC
AU - Colf, Leremy A.
AU - Bankovich, Alexander J.
AU - Hanick, Nicole A.
AU - Bowerman, Natalie A.
AU - Jones, Lindsay L.
AU - Kranz, David M M.
AU - Garcia, K. Christopher
N1 - Funding Information:
We thank Sean Juo for assistance with structure determination; Phil Holler and Susan Brophy for generation of the m6 TCR and the m31 L d mutants, respectively; and Herman Eisen for his advice and previous studies on the 2C system. We also gratefully acknowledge the staff and resources of the SSRL. L.C. is supported by an National Science Foundation predoctoral fellowship. This work was supported by NIH grants AI 48540 (K.C.G.) and GM55767 (D.M.K.). K.C.G. is also supported by the Keck Foundation and Howard Hughes Medical Institute.
PY - 2007/4/6
Y1 - 2007/4/6
N2 - αβ 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 Å structure of the 2C TCR complexed with its foreign ligand H-2Ld-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-2Kb-dEV8. 2C engages both shared and polymorphic residues on Ld and Kb, as well as the unrelated QL9 and dEV8 peptide antigens, in unique pair-wise contacts, resulting in greater structural complementarity with the Ld-QL9 complex. In the structure of an engineered, high-affinity 2C TCR variant bound to H-2Ld-QL9, the "wild-type" TCR-MHC binding orientation persists despite modified TCR-CDR3α 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.
AB - αβ 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 Å structure of the 2C TCR complexed with its foreign ligand H-2Ld-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-2Kb-dEV8. 2C engages both shared and polymorphic residues on Ld and Kb, as well as the unrelated QL9 and dEV8 peptide antigens, in unique pair-wise contacts, resulting in greater structural complementarity with the Ld-QL9 complex. In the structure of an engineered, high-affinity 2C TCR variant bound to H-2Ld-QL9, the "wild-type" TCR-MHC binding orientation persists despite modified TCR-CDR3α 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.
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U2 - 10.1016/j.cell.2007.01.048
DO - 10.1016/j.cell.2007.01.048
M3 - Article
C2 - 17418792
AN - SCOPUS:33947726614
VL - 129
SP - 135
EP - 146
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1
ER -