T cell receptor cross-reactivity directed by antigen-dependent tuning of peptide-MHC molecular flexibility.
T cell-mediated immunity requires T cell receptor (TCR) cross-reactivity, the mechanisms behind which remain incompletely elucidated. The alphabeta TCR A6 recognizes both the Tax (LLFGYPVYV) and Tel1p (MLWGYLQYV) peptides presented by the human class I MHC molecule HLA-A2. Here we found that although the two ligands are ideal structural mimics, they form substantially different interfaces with A6, with conformational differences in the peptide, the TCR, and unexpectedly, the MHC molecule. The differences between the Tax and Tel1p ternary complexes could not be predicted from the free peptide-MHC structures and are inconsistent with a traditional induced-fit mechanism. Instead, the differences were attributable to peptide and MHC molecular motion present in Tel1p-HLA-A2 but absent in Tax-HLA-A2. Differential "tuning" of the dynamic properties of HLA-A2 by the Tax and Tel1p peptides thus facilitates cross-recognition and impacts how structural diversity can be presented to and accommodated by receptors of the immune system.
Borbulevych
Oleg Y
OY
Department of Chemistry & Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA.
Piepenbrink
Kurt H
KH
Gloor
Brian E
BE
Scott
Daniel R
DR
Sommese
Ruth F
RF
Cole
David K
DK
Sewell
Andrew K
AK
Baker
Brian M
BM
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000276:immunology*; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000276:immunology*; D017433:Protein Structure, Secondary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000276:immunology*; D013816:Thermodynamics
D015789:HLA-A2 Antigen; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D017346:Protein Serine-Threonine Kinases; C513623:TEL1 protein, S cerevisiae