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A Technique to Simultaneously Visualize Virus-Specific CD8+ T Cells and Virus-Infected Cells In situ
Published on: August 13, 2009
Clearance of Sendai virus by CD8+ T cells requires direct targeting to virus-infected epithelium
1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Abstract:
Minimal numbers of CD8+ T cells are found in bronchoalveolar lavage (BAL) populations recovered from Sendai virus-infected mice that are homozygous (-/-) for a beta 2-microglobulin (beta 2-m) gene disruption. The prevalence of the CD8+ set was substantially increased in the pneumonic lungs of 8-12-week radiation chimeras made using substantially class I major histocompatibility complex (MHC) glycoprotein-negative beta 2-m (-/-) recipients and normal beta 2-m (+/+) bone marrow. Even so, the CD8+ (but not the CD4+) lymphocyte counts were still much lower than in the (+/+)-->(+/+) controls. The (+/+)-->(+/+) and (+/+)-->(-/-) chimeras cleared Sendai virus and potent virus-immune CD8+ cytotoxic T lymphocytes (CTL) specific for H-2Kb+viral nucleoprotein peptide were found in the BAL from both groups. However, following in vivo depletion of the CD4+ population, only the (+/+)-->(+/+) mice were able to deal with the infection. Similarly, adoptively transferred, H-2Kb-restricted CD8+ T cells from previously-primed (+/+) mice also failed to clear virus from the lungs of (+/+)-->(-/-) chimeras infected within 2 weeks of reconstitution with bone marrow, though they were effective in the (+/+)-->(+/+) controls. Sendai virus-immune CD8+ T cells are thus unable to eliminate virus-infected beta 2-m (-/-) lung epithelial cells that might be thought to be expressing very small amounts of either isolated class I heavy chain, or class I MHC glycoprotein that has bound beta 2-m derived from beta 2-m (+/+) T cells or macrophages present in the pneumonic lung. Furthermore, the CD8+ CTL that are being exposed to beta 2-m (+/+) stimulators in the BAL population cannot operate in some bystander mode to clear virus from respiratory epithelium.
Insights
Beta 2-microglobulin (beta 2-m) is crucial for CD8+ T cell function in clearing Sendai virus infections. Without sufficient beta 2-m, CD8+ cytotoxic T lymphocytes (CTLs) cannot eliminate virus-infected lung cells, impairing viral clearance.
Area of Science:
- Immunology
- Virology
- Cellular Biology
Background:
- Beta 2-microglobulin (beta 2-m) is essential for the expression of MHC class I glycoproteins.
- CD8+ T cells play a critical role in cell-mediated immunity against viral infections.
- Sendai virus infection in mice provides a model to study host immune responses in the respiratory tract.
Purpose of the Study:
- To investigate the role of beta 2-microglobulin in CD8+ T cell-mediated viral clearance.
- To determine if CD8+ cytotoxic T lymphocytes (CTLs) can eliminate virus-infected cells lacking sufficient beta 2-m.
- To elucidate the mechanisms of viral control in the context of MHC class I deficiency.
Main Methods:
- Generation of radiation bone marrow chimeras with varying beta 2-m genotypes.
- Infection of mice with Sendai virus.
- Analysis of bronchoalveolar lavage (BAL) and lung tissue for immune cell populations (CD4+, CD8+ T cells).
- Assessment of viral clearance and CTL activity in vivo and ex vivo.
Main Results:
- Mice lacking beta 2-m (beta 2-m-/-) showed minimal CD8+ T cells in bronchoalveolar lavage following Sendai virus infection.
- Radiation chimeras with beta 2-m deficient recipients had increased CD8+ T cells but still impaired viral clearance compared to controls.
- Adoptively transferred CD8+ T cells failed to clear virus in beta 2-m deficient recipients, indicating a critical role for beta 2-m in CTL function.
- CD4+ T cell depletion in wild-type mice also impaired viral clearance, highlighting the interplay between CD4+ and CD8+ T cells.
Conclusions:
- Beta 2-microglobulin is indispensable for the effector function of CD8+ cytotoxic T lymphocytes in clearing Sendai virus from the lungs.
- Virus-immune CD8+ T cells are unable to eliminate virus-infected lung epithelial cells in a beta 2-m deficient environment.
- The study underscores the necessity of MHC class I expression, dependent on beta 2-m, for effective viral immunity mediated by CD8+ T cells.
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