HLArestrictor—a tool for patient-specific predictions of HLA restriction elements and optimal epitopes within peptides
- 295 Downloads
Traditionally, T cell epitope discovery requires considerable amounts of tedious, slow, and costly experimental work. During the last decade, prediction tools have emerged as essential tools allowing researchers to select a manageable list of epitope candidates to test from a larger peptide, protein, or even proteome. However, no current tools address the complexity caused by the highly polymorphic nature of the restricting HLA molecules, which effectively individualizes T cell responses. To fill this gap, we here present an easy-to-use prediction tool named HLArestrictor (http://www.cbs.dtu.dk/services/HLArestrictor), which is based on the highly versatile and accurate NetMHCpan predictor, which here has been optimized for the identification of both the MHC restriction element and the corresponding minimal epitope of a T cell response in a given individual. As input, it requires high-resolution (i.e., 4-digit) HLA typing of the individual. HLArestrictor then predicts all 8–11mer peptide binders within one or more larger peptides and provides an overview of the predicted HLA restrictions and minimal epitopes. The method was tested on a large dataset of HIV IFNγ ELIspot peptide responses and was shown to identify HLA restrictions and minimal epitopes for about 90% of the positive peptide/patient pairs while rejecting more than 95% of the negative peptide-HLA pairs. Furthermore, for 18 peptide/HLA tetramer validated responses, HLArestrictor in all cases predicted both the HLA restriction element and minimal epitope. Thus, HLArestrictor should be a valuable tool in any T cell epitope discovery process aimed at identifying new epitopes from infectious diseases and other disease models.
KeywordsHLA restriction Epitope prediction MHC class I Peptide binding T cell epitope validation HLA tetramer validation
This work was supported by a NIH (National Institute of Health) grant (contract no. HHSN272200900045C) and The Danish Council for Independent Research Technology and Production Sciences (FTP 274-05-0582).
- Carlson JM, Heckerman D, Shani G (2009) Estimating false discovery rates for contingency tables. Microsoft Corporation TechReport. Available at http://research.microsoft.com/en-us/um/redmond/projects/MSCompBio/FalseDiscoveryRate/
- Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D, Thobakgale C, Chetty S, Rathnavalu P, Moore C, Pfafferott KJ, Hilton L, Zimbwa P, Moore S, Allen T, Brander C, Addo MM, Altfeld M, James I, Mallal S, Bunce M, Barber LD, Szinger J, Day C, Klenerman P, Mullins J, Korber B, Coovadia HM, Walker BD, Goulder PJ (2004) Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432:769–775CrossRefPubMedGoogle Scholar
- Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E, Reddy S, de Pierres C, Mncube Z, Mkhwanazi N, Bishop K, van der Stok M, Nair K, Khan N, Crawford H, Payne R, Leslie A, Prado J, Prendergast A, Frater J, McCarthy N, Brander C, Learn GH, Nickle D, Rousseau C, Coovadia H, Mullins JI, Heckerman D, Walker BD, Goulder P (2007) CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 13:46–53CrossRefPubMedGoogle Scholar
- Korber BTM, Brander C, Haynes BF, Koup R, Moore JP, Walker BD, Watkins DI (2009) HIV molecular immunology. Los Alamos National Laboratory, Theoretical Biology and Biophysics, Los Alamos, LA-UR 09-05941Google Scholar
- Payne RP, Kloverpris H, Sacha JB, Brumme Z, Brumme C, Buus S, Sims S, Hickling S, Riddell L, Chen F, Luzzi G, Edwards A, Phillips R, Prado JG, Goulder PJ (2010) Efficacious early antiviral activity of HIV Gag- and Pol-specific HLA-B 2705-restricted CD8+ T cells. J Virol 84:10543–10557CrossRefPubMedGoogle Scholar
- Sette A, Vitiello A, Reherman B, Fowler P, Nayersina R, Kast WM, Melief CJ, Oseroff C, Yuan L, Ruppert J, Sidney J, del Guercio MF, Southwood S, Kubo RT, Chesnut RW, Grey HM, Chisari FV (1994) The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol 153:5586–5592PubMedGoogle Scholar