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A virus-specific CD8+ T cell immunodominance hierarchy determined by antigen dose and precursor frequencies.

ABSTRACT: Immunodominance hierarchies are a substantial, but poorly understood, characteristic of CD8(+) T cell-mediated immunity. Factors influencing the differential responses to the influenza A virus nucleoprotein (NP(366-374)) and acid polymerase (PA(224-233)) peptides presented by H2D(b) have been analyzed by disabling (N5--> Q substitution) these peptides in their native configuration, then expressing them in the viral neuraminidase protein. This strategy of shifting epitopes within the same viral context resulted in an apparent equalization of D(b)NP(366) [epitope consisting of viral nucleoprotein (NP) amino acid residues 366-374 complexed with the H2D(b) MHC class I glycoprotein] and D(b)PA(224) (H2D(b)+PA(224-233)) epitope abundance after direct infection in vitro and induced reproducible changes in the magnitude of the D(b)NP(366)- and D(b)PA(224)-specific T cell subsets generated after infection of mice. Comparison of D(b)NP(366)- and D(b) PA(224)-specific CD8(+) T cell responses induced from the native configuration and from the viral neuraminidase stalk demonstrated that the size of both primary and secondary responses is influenced by relative epitope levels and that, at least after secondary challenge, the magnitude of responses is also determined by CD8(+) T cell precursor frequency. Thus, this immunodominance hierarchy is a direct function of antigen dose and T cell numbers.

SUBMITTER: La Gruta NL

PROVIDER: S-EPMC1348014 | biostudies-literature | 2006 Jan

REPOSITORIES: biostudies-literature

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A virus-specific CD8+ T cell immunodominance hierarchy determined by antigen dose and precursor frequencies.

La Gruta Nicole L NL Kedzierska Katherine K Pang Ken K Webby Richard R Davenport Miles M Chen Weisan W Turner Stephen J SJ Doherty Peter C PC

Proceedings of the National Academy of Sciences of the United States of America 20060117 4

Immunodominance hierarchies are a substantial, but poorly understood, characteristic of CD8(+) T cell-mediated immunity. Factors influencing the differential responses to the influenza A virus nucleoprotein (NP(366-374)) and acid polymerase (PA(224-233)) peptides presented by H2D(b) have been analyzed by disabling (N5--> Q substitution) these peptides in their native configuration, then expressing them in the viral neuraminidase protein. This strategy of shifting epitopes within the same viral c ...[more]

PMID: 16418289

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Project description:UnlabelledHepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with a poor prognosis and limited therapeutic options. To aid the development of novel immunological interventions, we studied the breadth, frequency, and tumor-infiltration of naturally occurring CD8(+) T-cell responses targeting several tumor-associated antigens (TAA). We used overlapping peptides spanning the entire alpha-fetoprotein (AFP), glypican-3 (GPC-3), melanoma-associated gene-A1 (MAGE-A1) and New York-esophageal squamous cell carcinoma-1 (NY-ESO-1) proteins and major-histocompatibility-complex-class-I-tetramers specific for epitopes of MAGE-A1 and NY-ESO-1 to analyze TAA-specific CD8(+) T-cell responses in a large cohort of HCC patients. After nonspecific expansion in vitro, we detected interferon-? (IFN-?)-producing CD8(+) T cells specific for all four TAA in the periphery as well as in liver and tumor tissue. These CD8(+) T-cell responses displayed clear immunodominance patterns within each TAA, but no consistent hierarchy was observed between different TAA. Importantly, the response breadth was highest in early-stage HCC and associated with patient survival. After antigen-specific expansion, TAA-specific CD8(+) T cells were detectable by tetramer staining but impaired in their ability to produce IFN-?. Furthermore, regulatory T cells (Treg) were increased in HCC lesions. Depletion of Treg from cultures improved TAA-specific CD8(+) T-cell proliferation but did not restore IFN-?-production.ConclusionNaturally occurring TAA-specific CD8(+) T-cell responses are present in patients with HCC and therefore constitute part of the normal T-cell repertoire. Moreover, the presence of these responses correlates with patient survival. However, the observation of impaired IFN-? production suggests that the efficacy of such responses is functionally limited. These findings support the development of strategies that aim to enhance the total TAA-specific CD8(+) T-cell response by therapeutic boosting and/or specificity diversification. However, further research will be required to help unlock the full potential of TAA-specific CD8(+) T-cell responses.

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A virus-specific CD8+ T cell immunodominance hierarchy determined by antigen dose and precursor frequencies.

Publications

A virus-specific CD8+ T cell immunodominance hierarchy determined by antigen dose and precursor frequencies.

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