Immunoproteasomes Shape Immunodominance Hierarchies of Antiviral CD8+ T Cells at the Levels of T Cell Repertoire and Presentation of Viral Antigens

doi:10.1084/jem.193.11.1319

Published online 4 June 2001.

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© The Rockefeller University Press, 0022-1007/2001/6/1319/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 11, June 4, 2001 1319-1326

Brief Definitive Report

Immunoproteasomes Shape Immunodominance Hierarchies of Antiviral CD8⁺ T Cells at the Levels of T Cell Repertoire and Presentation of Viral Antigens

Weisan Chen^a, Christopher C. Norbury^a, Yunjung Cho^a, Jonathan W. Yewdell^a, and Jack R. Bennink^a
^a Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Correspondence to: Jonathan W. Yewdell, Rm. 211, Bldg. 4, 4 Center Dr., MSC 0440, National Institutes of Health, Bethesda, MD 20892-0440. Tel:301-402-4602 Fax:301-402-7362 E-mail:jyewdell{at}nih.gov.

Vertebrates express three cytokine-inducible proteasome subunitsthat are incorporated in the place of their constitutively synthesizedcounterparts. There is increasing evidence that the set of peptidesgenerated by proteasomes containing these subunits (immunoproteasomes)differs from that produced by standard proteasomes. In thisstudy, we use mice lacking one of the immunoproteasome subunits(LMP2) to show that immunoproteasomes play an important rolein establishing the immunodominance hierarchy of CD8⁺ T cells(T_CD8+) responding to seven defined determinants in influenzavirus. In LMP2^-/- mice, responses to the two most dominant determinantsdrop precipitously, whereas responses to two subdominant determinantsare greatly enhanced. Adoptive transfer experiments with naivenormal and transgenic T_CD8+ reveal that the reduced immunogenicityof one determinant (PA_224–233) can be attributed to decreasedgeneration by antigen presenting cells (APCs), whereas the otherdeterminant (NP_366–374) is less immunogenic due to alterationsin the T_CD8+ repertoire, and not, as reported previously, tothe decreased capacity of LMP2^-/- APCs to generate the determinant.The enhanced response to one of the subdominant determinants(PB1F2_62–70) correlates with increased generation by LMP2^-^/-virus–infected cells. These findings indicate that inaddition to their effects on the presentation of foreign antigens,immunoproteasomes influence T_CD8+ responses by modifying therepertoire of responding T_CD8+.

Key Words: antigen processing, immunodominance, T cells, proteasome, repertoire

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Kesmir, C., Nussbaum, A. K., Schild, H., Detours, V., Brunak, S. (2002). Prediction of proteasome cleavage motifs by neural networks. Protein Eng Des Sel 15: 287-296 [Abstract] [Full Text]
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Boon, A. C. M., de Mutsert, G., Graus, Y. M. F., Fouchier, R. A. M., Sintnicolaas, K., Osterhaus, A. D. M. E., Rimmelzwaan, G. F. (2002). The Magnitude and Specificity of Influenza A Virus-Specific Cytotoxic T-Lymphocyte Responses in Humans Is Related to HLA-A and -B Phenotype. J. Virol. 76: 582-590 [Abstract] [Full Text]
Holtappels, R., Thomas, D., Podlech, J., Reddehase, M. J. (2002). Two Antigenic Peptides from Genes m123 and m164 of Murine Cytomegalovirus Quantitatively Dominate CD8 T-Cell Memory in the H-2d Haplotype. J. Virol. 76: 151-164 [Abstract] [Full Text]
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