Open AccessDual non-contiguous peptide occupancy of HLA class I evoke antiviral human CD8 T cell response and form neo-epitopes with self-antigens
Author(s) -
Ziwei Xiao,
Zhiyong Ye,
Vikeramjeet Singh Tadwal,
Meixin Shen,
Ee Chee Ren
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-05171-w
Subject(s) - epitope , human leukocyte antigen , cd8 , antigen , virology , dual (grammatical number) , peptide , biology , class (philosophy) , cytotoxic t cell , immunology , genetics , computer science , art , artificial intelligence , biochemistry , in vitro , literature
Host CD8 T cell response to viral infections involves recognition of 8–10-mer peptides presented by MHC-I molecules. However, proteasomes generate predominantly 2–7-mer peptides, but the role of these peptides is largely unknown. Here, we show that single short peptides of <8-mer from Latent Membrane Protein 2 (LMP2) of Epstein Barr Virus (EBV) can bind HLA-A*11:01 and stimulate CD8 + cells. Surprisingly, two peptide fragments between 4–7-mer derived from LMP2 (340–349) were able to complement each other, forming combination epitopes that can stimulate specific CD8 + T cell responses. Moreover, peptides from self-antigens can complement non-self peptides within the HLA binding cleft, forming neoepitopes. Solved structures of a tetra-complex comprising two peptides, HLA and β2-microglobulin revealed the free terminals of the two peptides to adopt an upward conformation directed towards the T cell receptor. Our results demonstrate a previously unknown mix-and-match combination of dual peptide occupancy in HLA that can generate vast combinatorial complexity.