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Journal of Virology, February 2006, p. 1222-1230, Vol. 80, No. 3
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.3.1222-1230.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Perforin-Deficient CD8+ T Cells Mediate Fatal Lymphocytic Choriomeningitis despite Impaired Cytokine Production

Pernille Storm, Christina Bartholdy, Maria Rathman Sørensen, Jan Pravsgaard Christensen, and Allan Randrup Thomsen*

Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark

Received 12 September 2005/ Accepted 9 November 2005

Intracerebral (i.c.) infection with lymphocytic choriomeningitis virus (LCMV) is one of the most studied models for virus-induced immunopathology, and based on results from perforin-deficient mice, it is currently assumed that fatal disease directly reflects perforin-mediated cell lysis. However, recent studies have revealed additional functional defects within the effector T cells of LCMV-infected perforin-deficient mice, raising the possibility that perforin may not be directly involved in mediating lethal disease. For this reason, we decided to reevaluate the role of perforin in determining the outcome of i.c. infection with LCMV. We confirmed that the expansion of virus-specific CD8+ T cells is unimpaired in perforin-deficient mice. However, despite the fact that the virus-specific CD8+ effector T cells in perforin-deficient mice are broadly impaired in their effector function, these mice invariably succumb to i.c. infection with LCMV strain Armstrong, although a few days later than matched wild-type mice. Upon further investigation, we found that this delay correlates with the delayed recruitment of inflammatory cells to the central nervous system (CNS). However, CD8+ effector T cells were not kept from the CNS by sequestering in infected extraneural organ sites such as liver or lungs. Thus, the observed dysfunctionality regarding the production of proinflammatory mediators probably results in the delayed recruitment of effector cells to the CNS, and this appears to be the main explanation for the delayed onset of fatal disease in perforin-deficient mice. However, once accumulated in the CNS, virus-specific CD8+ T cells can induce fatal CNS pathology despite the absence of perforin-mediated lysis and reduced capacity to produce several key cytokines.

* Corresponding author. Mailing address: Institute of Medical Microbiology and Immunology, The Panum Institute, 3C Blegdamsvej, DK-2200 Copenhagen N, Denmark. Phone: 45 35327871. Fax: 45 35327891. E-mail: a.r.thomsen{at}immi.ku.dk.

Journal of Virology, February 2006, p. 1222-1230, Vol. 80, No. 3
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.3.1222-1230.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Christensen, J. E., Simonsen, S., Fenger, C., Sorensen, M. R., Moos, T., Christensen, J. P., Finsen, B., Thomsen, A. R. (2009). Fulminant Lymphocytic Choriomeningitis Virus-Induced Inflammation of the CNS Involves a Cytokine-Chemokine-Cytokine-Chemokine Cascade. J. Immunol. 182: 1079-1087 [Abstract] [Full Text]  
  • Thomsen, A. R. (2009). Lymphocytic Choriomeningitis Virus-Induced Central Nervous System Disease: a Model for Studying the Role of Chemokines in Regulating the Acute Antiviral CD8+ T-Cell Response in an Immune-Privileged Organ. J. Virol. 83: 20-28 [Full Text]  
  • Crotty, S., McCausland, M. M., Aubert, R. D., Wherry, E. J., Ahmed, R. (2006). Hypogammaglobulinemia and exacerbated CD8 T-cell-mediated immunopathology in SAP-deficient mice with chronic LCMV infection mimics human XLP disease. Blood 108: 3085-3093 [Abstract] [Full Text]  


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