Dual non-contiguous peptide occupancy of HLA class I evoke antiviral human CD8 T cell response and form neo-epitopes with self-antigens

Abstract

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.

Unusual Placement of an EBV Epitope into the Groove of the Ankylosing Spondylitis-Associated HLA-B27 Allele Allows CD8+ T Cell Activation

“…Additional MD simulations of different peptide:HLA complexes could be very useful to confirm such a behaviour. However, this peptide conformation has been already disclosed, by the X-ray crystallography, for Tax8 an octameric peptide from human T cell lymphotropic virus-1 when complexed with the HLA-A2 molecule and, more recently, for a truncated 7-mer EBV peptide (LMP2 343-349) in the HLA-A*11:01 antigen-binding cleft [6,50]. Moreover, the peptidome analysis of the B*5101, a HLA class I allele associated with Behçet’s disease, displayed the presence of 10-mers with Pro or Ala at P2 together with their N-terminally truncated forms allowing to speculate about a non-canonical binding mode for these shorter peptides which leaves aside the A pocket [51].…”

Crystal structure of suboptimal viral fragments of Epstein Barr Virus Rta peptide-HLA complex that stimulate CD8 T cell response

“…Taken together, shorter peptides can complement each other when presented in tandem and may contribute in stabilizing the peptide-HLA complex. This notion is supported by a recent report suggesting that progressively truncated short peptides from immunogenic EBV antigen SSCSSCPLSK can still bind to HLA-I molecule and elicit CTLs despite having lower affinities 22 . Likewise, short peptides derived from L d peptide ligands, tum − and p2Ca are also shown to bind MHC class-I molecule as complementary pairs and stimulate specific CTLs 18 .…”

“…Previously, we have shown using short truncated peptides (SSCSSC, 6-mer and SSCPLSK, 7-mer) derived from EBV latent membrane protein-2 epitope, SSCSSCPLSK (LMP2, 340–349) restricted by HLA-A*11:01 to elicit a strong cytotoxic T lymphocytes when presented alone or in combination 22 . Notwithstanding the fact that EBV has the ability to persist and prevail in latent form, however, it will be interesting to investigate how the short peptides originating from the lytic cycle of EBV will behave.…”

“…Furthermore, two-thirds of the peptides generated by proteasome are less than 8-mer in length and only less than 15% of the proteasome breakdown products fall within an optimal range of 8–10 mer 20,21 . We have previously determined the occupancy of peptide binding groove for several antigens using synthetic peptides with serial truncation of peptides from both the N- and C-terminal ends 22 . In addition, there are reports demonstrating that non-contiguous peptide presentation by both MHC class I 23 and MHC class II 24 bring about an added intricacy in the production of T cell epitopes.…”

Immunodietica: interrogating the role of diet in autoimmune disease

“…Yet, peptides as long as 15 amino acids have been found to bind to some HLA class I alleles with affinity and stability comparable to those of canonical length 27,28 . Moreover, some 7 amino acid long peptides can stably bind to HLA class I and, curiously, peptides as short as 4 amino acids can also occupy the HLA class I binding groove in pairs, creating neoepitopes and eliciting CD8 + T cell responses 29 . HLA class II restricted epitopes, on the other hand, usually span 13-20 amino acids in length 30,31 .…”