How a single T cell receptor recognizes both self and foreign MHC.
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.
Colf
Leremy A
LA
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Bankovich
Alexander J
AJ
Hanick
Nicole A
NA
Bowerman
Natalie A
NA
Jones
Lindsay L
LL
Kranz
David M
DM
Garcia
K Christopher
KC
D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D022801:Complementarity Determining Regions / Q000378:metabolism; D018360:Crystallography, X-Ray; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D007519:Isoantigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000737:chemistry / Q000276:immunology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
D001324:Autoantigens; D022801:Complementarity Determining Regions; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D007519:Isoantigens; D008024:Ligands; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007655:Ketoglutarate Dehydrogenase Complex