Immune Function in Mice Lacking the Perforin Gene

Mice lacking the perforin gene were generated by using targeted gene disruption in embryonal stem cells. When infected with lymphocytic choriomeningitis virus (LCMV), perforin-less (-/-) mice showed clear signs of having mounted an immune response based on activation of CD8 T cells but were unable t...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1994-11, Vol.91 (23), p.10854-10858
Main Authors: Walsh, Craig M., Matloubian, Mehrdad, Liu, Chau-Ching, Ueda, Roanne, Kurahara, Carole G., Christensen, Julie L., Manley T. F. Huang, John Ding-E Young, Ahmed, Rafi, Clark, W. R.
Format: Article
Language:English
Subjects:
AIDS/HIV
Animals
Antigens, Surface - immunology
CD8-Positive T-Lymphocytes - immunology
Cytotoxicity
Cytotoxicity, Immunologic
fas Receptor
Female
Genes
Immunity (Disease)
Immunity, Cellular
Infections
Lymphocyte Count
Lymphocytes
Lymphocytic Choriomeningitis - immunology
Lymphocytic choriomeningitis virus
Male
Membrane Glycoproteins - physiology
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Knockout
Natural killer cells
Perforin
Pore Forming Cytotoxic Proteins
Rodents
Spleen cells
Splenocytes
Stem cells
T lymphocytes
T-Lymphocytes, Cytotoxic - immunology
Viruses
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Summary:Mice lacking the perforin gene were generated by using targeted gene disruption in embryonal stem cells. When infected with lymphocytic choriomeningitis virus (LCMV), perforin-less (-/-) mice showed clear signs of having mounted an immune response based on activation of CD8 T cells but were unable to clear the LCMV infection. This failure to eliminate virus was accompanied by a failure to generate spleen cells capable of lysing LCMV-infected fibroblasts in vitro. Spleen cells from LCMV-infected - / - mice were able to lyse hematopoietic target cells after exposure to phorbol 12-myristate 13-acetate and ionomycin, provided the target cells expressed the Fas antigen. Spleen cells from -/- mice also responded to alloantigen in mixed leukocyte culture by blastogenesis and proliferation. The resulting cells were able to lyse hematopoietic target cells, although not as well as spleen cells from + / + littermates sensitized in the same manner. However, lysis by - / - cells was again seen only if the target cells expressed Fas antigen. We conclude that perforin-less - / - mice retain and express the Fas lytic pathway as expressed in vitro but that this pathway is insufficient to clear an LCMV infection in vivo.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.91.23.10854