Affiliation:
1. Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
Abstract
Vertebrates express three cytokine-inducible proteasome subunits that are incorporated in the place of their constitutively synthesized counterparts. There is increasing evidence that the set of peptides generated by proteasomes containing these subunits (immunoproteasomes) differs from that produced by standard proteasomes. In this study, we use mice lacking one of the immunoproteasome subunits (LMP2) to show that immunoproteasomes play an important role in establishing the immunodominance hierarchy of CD8+ T cells (TCD8+) responding to seven defined determinants in influenza virus. In LMP2−/− mice, responses to the two most dominant determinants drop precipitously, whereas responses to two subdominant determinants are greatly enhanced. Adoptive transfer experiments with naive normal and transgenic TCD8+ reveal that the reduced immunogenicity of one determinant (PA224–233) can be attributed to decreased generation by antigen presenting cells (APCs), whereas the other determinant (NP366–374) is less immunogenic due to alterations in the TCD8+ repertoire, and not, as reported previously, to the decreased capacity of LMP2−/− APCs to generate the determinant. The enhanced response to one of the subdominant determinants (PB1F262–70) correlates with increased generation by LMP2−/− virus–infected cells. These findings indicate that in addition to their effects on the presentation of foreign antigens, immunoproteasomes influence TCD8+ responses by modifying the repertoire of responding TCD8+.
Publisher
Rockefeller University Press
Subject
Immunology,Immunology and Allergy
Cited by
218 articles.
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