The shaping of T cell receptor recognition by self-tolerance.
During selection of the T cell repertoire, the immune system navigates the subtle distinction between self-restriction and self-tolerance, yet how this is achieved is unclear. Here we describe how self-tolerance toward a trans-HLA (human leukocyte antigen) allotype shapes T cell receptor (TCR) recognition of an Epstein-Barr virus (EBV) determinant (FLRGRAYGL). The recognition of HLA-B8-FLRGRAYGL by two archetypal TCRs was compared. One was a publicly selected TCR, LC13, that is alloreactive with HLA-B44; the other, CF34, lacks HLA-B44 reactivity because it arises when HLA-B44 is coinherited in trans with HLA-B8. Whereas the alloreactive LC13 TCR docked at the C terminus of HLA-B8-FLRGRAYGL, the CF34 TCR docked at the N terminus of HLA-B8-FLRGRAYGL, which coincided with a polymorphic region between HLA-B8 and HLA-B44. The markedly contrasting footprints of the LC13 and CF34 TCRs provided a portrait of how self-tolerance shapes the specificity of TCRs selected into the immune repertoire.
Gras
Stephanie
S
Department of Biochemistry and Molecular Biology, The Protein Crystallography Unit, Monash University, Clayton, Victoria, Australia.
Burrows
Scott R
SR
Kjer-Nielsen
Lars
L
Clements
Craig S
CS
Liu
Yu Chih
YC
Sullivan
Lucy C
LC
Bell
Melissa J
MJ
Brooks
Andrew G
AG
Purcell
Anthony W
AW
McCluskey
James
J
Rossjohn
Jamie
J
D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology; D018360:Crystallography, X-Ray; D015795:HLA-B8 Antigen / Q000737:chemistry / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D020836:Protein Structure, Quaternary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*; D040681:Structural Homology, Protein; D020349:Surface Plasmon Resonance
D000956:Antigens, Viral; D015795:HLA-B8 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell