A Virus-Specific CD8⁺ T Cell Immunodominance Hierarchy Determined by Antigen Dose and Precursor Frequencies

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-01, Vol.103 (4), p.994-999
• Main Authors: La Gruta, Nicole L., Kedzierska, Katherine, Pang, Ken, Webby, Richard, Davenport, Miles, Chen, Weisan, Turner, Stephen J., Doherty, Peter C.
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Antigens - chemistry; Antigens - metabolism; Antigens, Viral - chemistry; Biological Sciences; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cytokines - metabolism; Dosage; Epitopes; Epitopes - chemistry; Female; Immune System; Immunologic Memory - immunology; Immunology; Infections; Influenza; Influenza A virus; Lung - virology; Lymphocyte Activation; Mice; Nucleoproteins - chemistry; Orthomyxoviridae; Orthomyxoviridae - genetics; Orthomyxoviridae - metabolism; Peptides; Peptides - chemistry; Receptors, Antigen, T-Cell - metabolism; Recombinant Proteins - chemistry; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; T cell antigen receptors; T cell receptors; T lymphocytes; T lymphoid precursor cells; T-Lymphocytes - immunology; Time Factors; Viral Proteins - chemistry; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0510429103

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.