title: TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys.
abstract: Many of the factors that contribute to CD8+ T cell immunodominance hierarchies during viral infection are known. However, the functional differences that exist between dominant and subdominant epitope-specific CD8+ T cells remain poorly understood. In this study, we characterized the phenotypic and functional differences between dominant and subdominant simian immunodeficiency virus (SIV) epitope-specific CD8+ T cells restricted by the major histocompatibility complex (MHC) class I allele Mamu-A*01 during acute and chronic SIV infection. Whole genome expression analyses during acute infection revealed that dominant SIV epitope-specific CD8+ T cells had a gene expression profile consistent with greater maturity and higher cytotoxic potential than subdominant epitope-specific CD8+ T cells. Flow-cytometric measurements of protein expression and anti-viral functionality during chronic infection confirmed these phenotypic and functional differences. Expression analyses of exhaustion-associated genes indicated that LAG-3 and CTLA-4 were more highly expressed in the dominant epitope-specific cells during acute SIV infection. Interestingly, only LAG-3 expression remained high during chronic infection in dominant epitope-specific cells. We also explored the binding interaction between peptide:MHC (pMHC) complexes and their cognate TCRs to determine their role in the establishment of immunodominance hierarchies. We found that epitope dominance was associated with higher TCR:pMHC affinity. These studies demonstrate that significant functional differences exist between dominant and subdominant epitope-specific CD8+ T cells within MHC-restricted immunodominance hierarchies and suggest that TCR:pMHC affinity may play an important role in determining the frequency and functionality of these cell populations. These findings advance our understanding of the regulation of T cell immunodominance and will aid HIV vaccine design.
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Osuna
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gonzalez
authors.affiliation: Children's Hospital Informatics Program, Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hsun-Hsien
authors.initials: HH
authors.lastname: Chang
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Amy Shi
authors.initials: AS
authors.lastname: Hung
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ehlinger
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Kara
authors.initials: K
authors.lastname: Anasti
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America; Department of Pathology, Duke University of Medicine, Durham, North Carolina, United States of America.
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002908:Chronic Disease; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D008253:Macaca mulatta; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; C110764:Mamu-A 01 antigen; D011948:Receptors, Antigen, T-Cell
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