Abstract's Details

How a Single T Cell Receptor Recognizes Both Self and Foreign MHC
Abstract ID	UMTG:4-2
Presenter	Leremy Colf
Presentation Type	SSRL/LCLS
Full Author List	L.A. Colf (1,2,3), A.J. Bankovich (1,2,3), N.A. Hanick (1,2,3), N.A. Bowerman (4), L.L. Jones (4), D.M. Kranz (4), K.C. Garcia (1,2,3)
Affiliations	(1) Howard Hughes Medical Institute (2) Stanford Dept. of Molecular and Cellular Physiology (3) Stanford Department of Structural Biology (4) University of Illinois Department of Biochemistry
Category	Bio/Life Sciences
Abstract	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-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-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.
Footnotes
Funding Acknowledgement	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.