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Updated: Sep 5, 2026
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Immune function in mice lacking the perforin gene
C M Walsh1, M Matloubian, C C Liu
1Department of Biology, University of California, Los Angeles 90024.
Abstract:
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.
Insights
Mice lacking the perforin gene could not clear lymphocytic choriomeningitis virus (LCMV) infection. The Fas lytic pathway was retained but insufficient for viral clearance in vivo.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Perforin is a key protein in the immune system's cytotoxic response.
- Cytotoxic T lymphocytes (CTLs) play a crucial role in viral clearance.
- The Fas pathway is an alternative cytotoxic mechanism.
Purpose of the Study:
- To investigate the role of perforin in viral clearance using a mouse model.
- To determine if the Fas pathway can compensate for the lack of perforin during viral infection.
- To assess the in vivo efficacy of the Fas lytic pathway.
Main Methods:
- Generation of perforin-deficient mice using gene targeting.
- Infection of mice with lymphocytic choriomeningitis virus (LCMV).
- Analysis of immune responses, including CD8 T cell activation and cytotoxic activity in vitro and in vivo.
- Assessment of Fas antigen expression on target cells.
Main Results:
- Perforin-deficient mice mounted an immune response but failed to clear LCMV infection.
- Spleen cells from these mice could not lyse LCMV-infected fibroblasts in vitro.
- Spleen cells showed Fas-dependent lysis of hematopoietic cells in vitro after stimulation.
- The Fas pathway was insufficient for complete viral clearance in vivo.
Conclusions:
- Perforin is essential for effective clearance of LCMV infection in mice.
- While the Fas lytic pathway is functional in perforin-deficient mice, it is insufficient for in vivo viral elimination.
- These findings highlight the critical role of perforin in cell-mediated immunity against viral pathogens.
