Peptide Binding motif Height of a column equal to I Relative height of a letter is p High information positions HLA-A0201
NetMHC-3.0 www.cbs.dtu.dk/services/NetMHC 62 ANN and 68 PSSM Covering Human, Primate and Mouse MHC Predictions can be made for 8-11 mer petides
The IMGT/HLA Sequence Database currently encompass more than 1500 HLA class I proteins Source: http://www.anthonynolan.com/HIG/index.html HLA polymorphism
< 70 HLA alleles are characterized by binding data Reliable MHC class I binding predictions (NetMHC-3.0) for 60 HLA A and B molecules No methods for HLA-C, and HLA-E Long way to over 1500!
More MHC molecules: more diversity in the presented peptides 1% probability that MHC molecule presents a peptide Different hosts sample different peptides from same pathogen.
HLA polymorphism Few human beings will share the same set of HLA alleles –Different persons will react to a pathogen infection in a non-similar manner A CTL based vaccine must include epitopes specific for each HLA allele in a population –A CTL based vaccine must consist of ~1000 HLA class I epitopes and ~5000 class II epitopes
Logos of HLA-A alleles O Lund et al., Immunogenetics. 2004 55:797-810 A2 supertype
Clustering of HLA alleles O Lund et al., Immunogenetics. 2004 55:797-810
Supertypes. What are they good for? Alleles with in supertypes present the same set of peptides! Is this really so? –Less that 50% of A6802 binders will bind to A0201! –Less than 33% of A0201 binders will bind to A6802!
Pan-specific method The contact residues are defined as being within 4.0 Å of the peptide in any of a representative set of HLA-A and -B structures with nonamer peptides. Only polymorphic residues from A, B, and C alleles are included Pseudo-sequence consisting of 34 amino acid residues. Include polymorphic residues in potential contact with the bound peptide
HLA class II polymorphism More than 2000 HLA class II allele combinations –HLA-DR –HLA-DQ –HLA-DP Only data for 14 of the more than 500 known HLA-DR allele (< 3%) No data for HLA-DQ and HLA-DP
Class II MHC binding MHC class II binds peptides in the class II antigen presentation pathway Binds peptides of length 9-18 (even whole proteins can bind!) Binding cleft is open Binding core is 9 aa
MHC class II binding motif 100 10mer peptides 2 100 ~10 30 combinations Monte Carlo simulations can do it
NetMHC-IIpan Train on peptide:MHC sequences –As for the NetMHCpan for class I Need to identify peptide core! –Use SMM-align
MHC pseudo sequence The contact residues are defined as being within 4.0 Å of the peptide in any of a representative set of HLA-DR, -DQ, and DP structures with peptides. Only polymorphic residues are included Pseudo-sequence consisting of 25 amino acid residues. Include polymorphic residues in potential contact with the bound peptide
Bovin HLA-DR epitopes (data W. Brown and J. Norimine) So even cows are like humans!
Epitope based vaccines and diagnostics Challenges Identify epitopes in pathogen genome A small viral genome contains >> 1000 potential CTL epitopes HLA diversity No two humans will induce the same reaction to a pathogen infection Viral escape No two viral strains will “host” the same set of T cell epitopes