T cell allorecognition via molecular mimicry

Whitney Alison Macdonald, Zhenjun Chen, Stephanie Gras, Julia Kate Archbold, Fleur Elizabeth Tynan, Craig Steven Clements, Mandvi Bharadwaj, Lars Kjer-Nielsen, Philippa M Saunders, Matthew Charles James Wilce, Fran Crawford, Brian Stadinsky, David Jackson, Andrew Brooks, Anthony Wayne Purcell, John Kappler, Scott R Burrows, Jamie Rossjohn, James McCluskey

Research output: Contribution to journalArticleResearchpeer-review

185 Citations (Scopus)

Abstract

T cells often alloreact with foreign human leukocyte antigens (HLA). Here we showed the LC13 T cell receptor (TCR), selected for recognition on self-HLA-B( *)0801 bound to a viral peptide, alloreacts with B44 allotypes (HLA-B( *)4402 and HLA-B( *)4405) bound to two different allopeptides. Despite extensive polymorphism between HLA-B( *)0801, HLA-B( *)4402, and HLA-B( *)4405 and the disparate sequences of the viral and allopeptides, the LC13 TCR engaged these peptide-HLA (pHLA) complexes identically, accommodating mimicry of the viral peptide by the allopeptide. The viral and allopeptides adopted similar conformations only after TCR ligation, revealing an induced-fit mechanism of molecular mimicry. The LC13 T cells did not alloreact against HLA-B( *)4403, and the single residue polymorphism between HLA-B( *)4402 and HLA-B( *)4403 affected the plasticity of the allopeptide, revealing that molecular mimicry was associated with TCR specificity. Accordingly, molecular mimicry that is HLA and peptide dependent is a mechanism for human T cell alloreactivity between disparate cognate and allogeneic pHLA complexes.
Original languageEnglish
Pages (from-to)897 - 908
Number of pages12
JournalImmunity
Volume31
Issue number6
DOIs
Publication statusPublished - 2009

Cite this