T cell allorecognition via molecular mimicry.
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.
Macdonald
Whitney A
WA
The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
Chen
Zhenjun
Z
Gras
Stephanie
S
Archbold
Julia K
JK
Tynan
Fleur E
FE
Clements
Craig S
CS
Bharadwaj
Mandvi
M
Kjer-Nielsen
Lars
L
Saunders
Philippa M
PM
Wilce
Matthew C J
MC
Crawford
Fran
F
Stadinsky
Brian
B
Jackson
David
D
Brooks
Andrew G
AG
Purcell
Anthony W
AW
Kappler
John W
JW
Burrows
Scott R
SR
Rossjohn
Jamie
J
McCluskey
James
J
D002460:Cell Line; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology*; D015795:HLA-B8 Antigen; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D018716:Molecular Mimicry / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
C508151:EBNA-3A antigen; D019309:Epstein-Barr Virus Nuclear Antigens; D015235:HLA-B Antigens; C509422:HLA-B*08:01 antigen; D015795:HLA-B8 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell