Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2001 Jun 4;193(11):1319-26.
doi: 10.1084/jem.193.11.1319.

Immunoproteasomes shape immunodominance hierarchies of antiviral CD8(+) T cells at the levels of T cell repertoire and presentation of viral antigens

W Chen  1 , C C Norbury, Y Cho, J W Yewdell, J R Bennink
Affiliations

Immunoproteasomes shape immunodominance hierarchies of antiviral CD8(+) T cells at the levels of T cell repertoire and presentation of viral antigens

W Chen et al. J Exp Med. .

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 (T(CD8+)) 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 T(CD8+) reveal that the reduced immunogenicity of one determinant (PA(224-233)) can be attributed to decreased generation by antigen presenting cells (APCs), whereas the other determinant (NP(366-374)) is less immunogenic due to alterations in the T(CD8+) 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 (PB1F2(62-70)) 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 T(CD8+) responses by modifying the repertoire of responding T(CD8+).

PubMed Disclaimer

Figures

Figure 1
Figure 1
Immunodominance hierarchy to IV infection in B6 and LMP2−/− mice. Spleen and peritoneal cells were prepared at various times after IV priming and their determinant-specific responses were assessed by ICS using a panel of synthetic peptides corresponding to defined H-2b–restricted determinants. All responses were normalized by subtracting background values obtained using cells receiving no peptides. In this experiment, twice as many TCD8+ were recovered from B6 mice than from LMP2−/− mice.
Figure 4
Figure 4
IV-specific responses of transferred naive LMP2−/− T cells. CD90-enriched spleen cells from naive LMP2−/− mice were transferred into either naive B6.SJL or B6 mice followed by IV priming. 7 d later, both the host and donor cells were assayed for ICS and CD45.2 expression. The determinant-specific hierarchy among host (left) and donor (right) splenic TCD8+ is shown. Data were processed as described in the Fig. 2 legend. Note the 10-fold difference in the Ag-specific TCD8+ scale.
Figure 2
Figure 2
IV-specific responses of naive host and donor T cells. CD90-enriched spleen cells from naive B6.SJL were transferred into either normal B6 or LMP2−/− mice followed by IV infection. After 7 d, both host and donor cells were assayed for ICS and CD45.1 expression. Donor- and host-derived NP366–374-specific TCD8+ were also tested for NP366–374-tetramer staining and CD45.1 expression. Panel A shows typical NP366–374-tetramer staining of spleen cells (left). The background-positive staining on naive B6 spleen cells was <0.5%. Tetramer-positive cells were gated and displayed as CD45.1 positive (donor) and negative (host) (middle). The percentage of each group was then plotted as the fraction of tetramer positive cells (right). B and C show, respectively, the determinant-specific hierarchy of host and donor cells. Both are shown as the total antigen-specific cell number, either per spleen or per peritoneum after subtracting background values obtained from the no peptide control for each mouse. Data represent the average values from two individual mice.
Figure 3
Figure 3
Activation of adoptively transferred transgenic TCD8+. Purified TCD8+ from F5 TCR transgenic mice were transferred into B6 or LMP2−/− mice infected with NT60, X31 (control), or left uninfected as indicated. Cells were assessed by flow cytometry for activation based on enhanced binding of a CD25-specific mAb or decreased binding of a CD62-specific mAb.
Figure 5
Figure 5
Kinetics of antigen presentation of B6 and LMP2−/− cells. The efficiency of antigen presentation was determined by the capacity of cells to activate short-term antigen-specific TCD8+ as determined by ICS. (A) Kinetics of antigen presentation of Con A blasts to NP366–374-specific TCD8+ (left) or PB1F262–70-specific TCD8+ (right). (B) Kinetics of antigen presentation of cells as indicated to NP366–374-specific TCD8+. PEC, peritoneal cavity.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Rock K.L., Gramm C., Rothstein L., Clark K., Stein R., Dick L., Hwang D., Goldberg A.L. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994;78:761–771. - PubMed
    1. Voges D., Zwickl P., Baumeister W. The 26S proteasomea molecular machine designed for controlled proteolysis. Annu. Rev. Biochem. 1999;68:1015–1068. - PubMed
    1. Groll M., Bajorek M., Kohler A., Moroder L., Rubin D.M., Huber R., Glickman M.H., Finley D. A gated channel into the proteasome core particle. Nat. Struct. Biol. 2000;7:1062–1067. - PubMed
    1. Hershko A., Ciechanover A. The ubiquitin system. Annu. Rev. Biochem. 1998;67:425–479. - PubMed
    1. Tanaka K., Kasahara M. The MHC class I ligand-generating systemroles of immunoproteasomes and the interferon-gamma-inducible proteasome activator PA28. Immunol. Rev. 1998;163:161–176. - PubMed

Publication types

MeSH terms