Perforin-deficient CD8+ T cells mediate fatal lymphocytic choriomeningitis despite impaired cytokine production.
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.
Storm
Pernille
P
Institute of Medical Microbiology and Immunology, The Panum Institute, 3C Blegdamsvej, DK-2200 Copenhagen N, Denmark.
Bartholdy
Christina
C
Sørensen
Maria Rathman
MR
Christensen
Jan Pravsgaard
JP
Thomsen
Allan Randrup
AR
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D008216:Lymphocytic Choriomeningitis / Q000209:etiology / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000472:pathogenicity; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052899:Pore Forming Cytotoxic Proteins
D016207:Cytokines; D018836:Inflammation Mediators; D039041:Integrin alpha4beta1; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse; D007371:Interferon-gamma