Giuseppe
Emeritus
[Source: PNAS, full text: (LINK). Abstract, edited.]
Systematic identification of immunodominant CD8<SUP>+</SUP> T-cell responses to influenza A virus in HLA-A2 individuals
Immunodominant T-cell responses are important for virus clearance. However, the identification of immunodominant T-cell peptide + HLA glycoprotein epitopes has been hindered by the extent of HLA polymorphism and the limitations of predictive algorithms. A simple, systematic approach has been used here to screen for immunodominant CD8<SUP>+</SUP> T-cell specificities. The analysis targeted healthy HLA-A2<SUP>+</SUP> donors to allow comparison with responses to the well-studied influenza matrix protein 1 epitope. Although influenza matrix protein 1 was consistently detected in all individual samples in our study, the response to this epitope was only immunodominant in three of eight, whereas for the other five, prominent CD8<SUP>+</SUP> T-cell responses tended to focus on various peptides from the influenza nucleoprotein that were not presented by HLA-A2. Importantly, with the four immunodominant T-cell epitopes identified here, only one would have been detected by the current prediction programs. The other three peptides would have been either considered too long or classified as not containing typical HLA binding motifs. Our data stress the importance of systematic analysis for discovering HLA-dependent, immunodominant CD8<SUP>+</SUP> T-cell epitopes derived from viruses and tumors. Focusing on HLA-A2 and predictive algorithms may be too limiting as we seek to develop targeted immunotherapy and vaccine strategies that depend on T cell-mediated immunity.
Footnotes
- ------ Chao Wu<SUP>a</SUP>,<SUP>b</SUP>,
- Damien Zanker<SUP>b</SUP>,
- Sophie Valkenburg<SUP>c</SUP>,
- Bee Tan<SUP>b</SUP>,
- Katherine Kedzierska<SUP>c</SUP>,
- Quan Ming Zou<SUP>a</SUP>,
- Peter C. Doherty<SUP>c</SUP>,<SUP>1</SUP>, and
- Weisan Chen<SUP>b</SUP>,<SUP>1</SUP>
- <SUP>a</SUP>Department of Clinical Microbiology and Immunology, Third Military Medical University, Chongqing 400038, China;
- <SUP>b</SUP>Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria 3084, Australia; and
- <SUP>c</SUP>Department of Microbiology and Immunology, Melbourne University, Parkville, Victoria 3052, Australia
- Contributed by Peter C. Doherty, April 11, 2011 (sent for review March 15, 2011)
Immunodominant T-cell responses are important for virus clearance. However, the identification of immunodominant T-cell peptide + HLA glycoprotein epitopes has been hindered by the extent of HLA polymorphism and the limitations of predictive algorithms. A simple, systematic approach has been used here to screen for immunodominant CD8<SUP>+</SUP> T-cell specificities. The analysis targeted healthy HLA-A2<SUP>+</SUP> donors to allow comparison with responses to the well-studied influenza matrix protein 1 epitope. Although influenza matrix protein 1 was consistently detected in all individual samples in our study, the response to this epitope was only immunodominant in three of eight, whereas for the other five, prominent CD8<SUP>+</SUP> T-cell responses tended to focus on various peptides from the influenza nucleoprotein that were not presented by HLA-A2. Importantly, with the four immunodominant T-cell epitopes identified here, only one would have been detected by the current prediction programs. The other three peptides would have been either considered too long or classified as not containing typical HLA binding motifs. Our data stress the importance of systematic analysis for discovering HLA-dependent, immunodominant CD8<SUP>+</SUP> T-cell epitopes derived from viruses and tumors. Focusing on HLA-A2 and predictive algorithms may be too limiting as we seek to develop targeted immunotherapy and vaccine strategies that depend on T cell-mediated immunity.
Footnotes
- <SUP>1</SUP>To whom correspondence may be addressed. E-mail: pcd@unimelb.edu.au or weisan.chen@ludwig.edu.au.
- Author contributions: C.W., D.Z., S.V., B.T., K.K., P.C.D., and W.C. designed research; C.W., D.Z., S.V., and B.T. performed research; S.V., K.K., Q.M.Z., P.C.D., and W.C. analyzed data; and K.K., P.C.D., and W.C. wrote the paper.
- The authors declare no conflict of interest.
- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1105624108/-/DCSupplemental.