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TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys.

Publication ,  Journal Article
Osuna, CE; Gonzalez, AM; Chang, H-H; Hung, AS; Ehlinger, E; Anasti, K; Alam, SM; Letvin, NL
Published in: PLoS Pathog
April 2014

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.

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Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

April 2014

Volume

10

Issue

4

Start / End Page

e1004069

Location

United States

Related Subject Headings

  • Virology
  • Simian immunodeficiency virus
  • Simian Immunodeficiency Virus
  • Simian Acquired Immunodeficiency Syndrome
  • Receptors, Antigen, T-Cell
  • Macaca mulatta
  • Histocompatibility Antigens Class I
  • Epitopes, T-Lymphocyte
  • Chronic Disease
  • CD8-Positive T-Lymphocytes
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Osuna, C. E., Gonzalez, A. M., Chang, H.-H., Hung, A. S., Ehlinger, E., Anasti, K., … Letvin, N. L. (2014). TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys. PLoS Pathog, 10(4), e1004069. https://doi.org/10.1371/journal.ppat.1004069
Osuna, Christa E., Ana Maria Gonzalez, Hsun-Hsien Chang, Amy Shi Hung, Elizabeth Ehlinger, Kara Anasti, S Munir Alam, and Norman L. Letvin. “TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys.PLoS Pathog 10, no. 4 (April 2014): e1004069. https://doi.org/10.1371/journal.ppat.1004069.
Osuna CE, Gonzalez AM, Chang H-H, Hung AS, Ehlinger E, Anasti K, et al. TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys. PLoS Pathog. 2014 Apr;10(4):e1004069.
Osuna, Christa E., et al. “TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys.PLoS Pathog, vol. 10, no. 4, Apr. 2014, p. e1004069. Pubmed, doi:10.1371/journal.ppat.1004069.
Osuna CE, Gonzalez AM, Chang H-H, Hung AS, Ehlinger E, Anasti K, Alam SM, Letvin NL. TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys. PLoS Pathog. 2014 Apr;10(4):e1004069.

Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

April 2014

Volume

10

Issue

4

Start / End Page

e1004069

Location

United States

Related Subject Headings

  • Virology
  • Simian immunodeficiency virus
  • Simian Immunodeficiency Virus
  • Simian Acquired Immunodeficiency Syndrome
  • Receptors, Antigen, T-Cell
  • Macaca mulatta
  • Histocompatibility Antigens Class I
  • Epitopes, T-Lymphocyte
  • Chronic Disease
  • CD8-Positive T-Lymphocytes