Movatterモバイル変換

[0]ホーム
URL:

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

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Atypon full text link Atypon Free PMC article
Full text links

Actions

Share

.2006 Sep;80(17):8627-38.
doi: 10.1128/JVI.00855-06.

Role of Bim in regulating CD8+ T-cell responses during chronic viral infection

Affiliations

Role of Bim in regulating CD8+ T-cell responses during chronic viral infection

Jason M Grayson et al. J Virol.2006 Sep.

Abstract

Apoptosis is critical for the development and maintenance of the immune system. The proapoptotic Bcl-2 family member Bim is important for normal immune system homeostasis. Although previous experiments have shown that Bim is critical for the apoptosis of antigen-specific CD8(+) T cells during acute viral infection, the role of Bim during chronic viral infection is unclear. Using lymphocytic choriomeningitis virus clone 13 infection of mice, we demonstrate a role for Bim in CD8(+) T-cell apoptosis during chronic viral infection. Enumeration of antigen-specific CD8(+) T cells by major histocompatibility complex class I tetramer staining revealed that CD8(+) D(b)NP396-404(+) T cells, which undergo extensive deletion in wild-type mice, exhibited almost no decrease in Bim mutant mice. This contrasts with CD8(+) D(b)GP33-41(+) and CD8(+) D(b)GP276-286(+) T cells that underwent similar decreases in numbers in both Bim mutant and wild-type mice. Increased numbers of CD8(+) D(b)NP396-404(+) T cells in Bim mutant mice were due to lack of apoptosis and could not be explained by altered proliferation, differential homing to tissues, or increased help from CD4(+) T cells. When viral titers were examined, high levels were initially observed in both groups, but in Bim mutant mice, clearance from the spleen and sera was slightly accelerated. These experiments demonstrate the critical role of Bim during chronic viral infection to down-regulate CD8(+) T-cell responses and have implications for designing strategies for optimizing immunotherapies during situations where antigen persists, such as chronic infection, autoimmune syndromes, and cancer.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
Chronic viral infection of Bim mutant mice results in alteration of the immunodominance hierarchy and increased numbers of NP396-404-specific CD8+ T cells. Wild-type or Bim mutant mice were infected with LCMV clone 13. (A) At the indicated time points, mice were sacrificed, the spleen was removed, and cells were stained with anti-CD8α, anti-CD44, and either DbGP33-41, DbNP396-404, or DbGP276-286 MHC class I tetramer. The numbers in the upper quadrants indicate the percentages of total CD8+ T cells that each population comprises. The numbers of activated (B) or antigen-specific (C to E) CD8+ T cells were quantitated, and the averages and standard deviations are shown. Five to twelve mice were analyzed at each time point. *, significant difference between wild-type and Bim mutant mice, with aP value of ≤0.05.
FIG. 2.
FIG. 2.
Acute viral infection of Bim mutant mice results in increased numbers of antigen-specific CD8+ memory T cells. Wild-type or Bim mutant mice were infected with LCMV Armstrong. (A) At the indicated time points, mice were sacrificed, spleens were removed, and cells were stained with anti-CD8α, anti-CD44, and either DbGP33-41, DbNP396-404, or DbGP276-286 MHC class I tetramer. The numbers of activated (A) or antigen-specific (B to D) CD8+ T cells were quantitated, and the averages and standard deviations are shown. Five to ten mice were analyzed at each time point. *, significant difference between wild-type and Bim mutant mice, with aP value of ≤0.05.
FIG. 3.
FIG. 3.
Chronic viral infection of Bim mutant mice results in increased numbers of IFN-γ+ and TNF-α+ NP396-404-specific CD8+ T cells. Wild-type or Bim mutant mice were infected with LCMV clone 13. (A) On day 8 postinfection, mice were sacrificed, the spleens were removed, and cells were stimulated with the indicated peptide and then stained with anti-CD8α, anti-IFN-γ, and anti-TNF-α. The dot plots are gated on CD8+ T cells, and the number in the plot indicates the percentage of CD8+ T cells that are present in that region. (B) Mice were sacrificed at other time points, and the numbers of cytokine-producing CD8+ T cells were quantitated. The averages and standard deviations are shown. Five to twelve mice were analyzed at each time point. *, significant difference between wild-type and Bim mutant mice, with aP value of ≤0.05.
FIG. 4.
FIG. 4.
Chronic viral infection of Bim mutant mice results in increased numbers of NP396-404-specific CD8+ T cells in the liver. Wild-type or Bim mutant mice were infected with LCMV clone 13. At the indicated time points, mice were sacrificed, livers were removed, and cells were stained with anti-CD8α and anti-CD44 (A) and either DbGP33-41 (B), DbNP396-404 (C), or DbGP276-286 (D) MHC class I tetramer. The numbers of activated (A) or antigen-specific (B to D) CD8+ T cells were quantitated, and the averages and standard deviations are shown. Five to twelve mice were analyzed at each time point. *, significant difference between wild-type and Bim mutant mice, with aP value of ≤0.05.
FIG. 5.
FIG. 5.
Bim mutation does not affect CD4+ T-cell responses during chronic viral infection. Wild-type or Bim mutant mice were infected with LCMV clone 13. At the indicated time point postinfection, mice were sacrificed, spleens were removed, and cells were either stained with anti-CD4 and anti-CD44 antibodies (A) or stimulated with GP61-80 peptide and then stained with anti-CD4 anti-IFN-γ and anti-TNF-α (B and C). The number of cytokine-producing CD4+ T cells was quantitated, and the averages and standard deviations are shown. Five to twelve mice were analyzed at each time point. *, significant difference between wild-type and Bim mutant mice, with aP value of ≤0.05.
FIG. 6.
FIG. 6.
Clone 13 infection generates high levels of virus in Bim mutant mice. Wild-type or Bim mutant mice were infected with LCMV clone 13. At the indicated time point, mice were sacrificed and the serum (A), spleen (B), liver (C), and kidneys (D) were isolated, and virus was quantitated by plaque assay. Each symbol indicates the value for one mouse. Five to twelve mice were analyzed at each time point. *, significant difference between wild-type and Bim mutant mice, with aP value of ≤0.05.
FIG. 7.
FIG. 7.
Antigen-specific CD8+ T cells from Bim mutant mice enter the early stages of apoptosis. Wild-type or Bim mutant mice were infected with LCMV clone 13. On day 15 postinfection, mice were sacrificed, spleens were removed, and cells were either stained with anti-CD8 and anti-CD44 (A) or MHC class I tetramer (B to E). A representative dot plot is presented for DbNP396-404+ CD8+ T cells. Direct ex vivo apoptosis was assessed by staining with annexin V and 7-AAD. The numbers in each dot plot indicate the percentage of each population that falls into that region. The numbers of cells that fall into each quadrant were determined for six mice and are plotted as averages and standard deviations. *, significant difference between wild-type and Bim mutant mice, with aP value of ≤0.05.
FIG. 8.
FIG. 8.
Reduced proliferation of antigen-specific CD8+ T cells from Bim mutant mice during the deletion phase. Wild-type or Bim mutant mice were infected with LCMV clone 13. Proliferation during the deletion phase was assessed by including BrdU (0.8 mg/ml) in the drinking water of mice from day 15 to day 25 after infection. Splenocytes were isolated on day 25 postinfection and stained with anti-CD8α, DbNP396-404, and anti-BrdU antibody. The plots are gated on CD8+ DbNP396-404+ cells, and the number on the dot plot indicates the percentage of antigen-specific cells that are BrdU+. To determine the proliferation in other populations, splenocytes were stained with either anti-BrdU and anti-CD8α antibodies (A) or anti-CD44 antibodies (B) and DbGP33-41, DbNP396-404, or DbGP276-286 MHC class I tetramers. The percentages of BrdU+ cells were determined and plotted as averages and standard deviations. Five mice were analyzed for each genotype. *, significant difference between wild-type and Bim mutant mice, with aP value of ≤0.05.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ahmed, R., A. Salmi, L. D. Butler, J. M. Chiller, and M. B. Oldstone. 1984. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 160:521-540. - PMC - PubMed
    1. Alexander-Miller, M. A., M. A. Derby, A. Sarin, P. A. Henkart, and J. A. Berzofsky. 1998. Supraoptimal peptide-major histocompatibility complex causes a decrease in bc1-2 levels and allows tumor necrosis factor alpha receptor II-mediated apoptosis of cytotoxic T lymphocytes. J. Exp. Med. 188:1391-1399. - PMC - PubMed
    1. Badovinac, V. P., B. B. Porter, and J. T. Harty. 2002. Programmed contraction of CD8(+) T cells after infection. Nat. Immunol. 3:619-626. - PubMed
    1. Bouillet, P., S. Cory, L. C. Zhang, A. Strasser, and J. M. Adams. 2001. Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. Dev. Cell 1:645-653. - PubMed
    1. Bouillet, P., D. Metcalf, D. C. Huang, D. M. Tarlinton, T. W. Kay, F. Kontgen, J. M. Adams, and A. Strasser. 1999. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286:1735-1738. - PubMed

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full text links
Atypon full text link Atypon Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp