How a Single T Cell Receptor Recognizes Both Self and Foreign MHC

Leremy A. Colf, Alexander J. Bankovich, Nicole A. Hanick, Natalie A. Bowerman, Lindsay L. Jones, David M M. Kranz, K. Christopher Garcia

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)135-146
Number of pages12
Issue number1
StatePublished - Apr 6 2007

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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