White DW, MacNeil A, Busch DH, Pilip IM, Pamer EG & Harty JT. Perforin-deficient CD8+ T cells: In vivo priming and antigen-specific immunity against Listeria monocytogenes. J Immunol162: 980-988

Section of Infectious Diseases , Yale University, New Haven, Connecticut, United States
The Journal of Immunology (Impact Factor: 4.92). 02/1999; 162(2):980-8.
Source: PubMed


CD8+ T cells require perforin to mediate immunity against some, but not all, intracellular pathogens. Previous studies with H-2b MHC perforin gene knockout (PO) mice revealed both perforin-dependent and perforin-independent pathways of CD8+ T cell-mediated immunity to Listeria monocytogenes (LM). In this study, we address two previously unresolved issues regarding the requirement for perforin in antilisterial immunity: 1) Is CD8+ T cell-mediated, perforin-independent immunity specific for a single Ag or generalizable to multiple Ags? 2) Is there a deficiency in the priming of the CD8+ T cell compartment of PO mice following an immunizing challenge with LM? We used H-2d MHC PO mice to generate CD8+ T cell lines individually specific for three known Ags expressed by a recombinant strain of virulent LM. Adoptive transfer experiments into BALB/c host mice revealed that immunity can be mediated by PO CD8+ T cells specific for all Ags examined, indicating that perforin-independent immunity is not limited to CD8+ T cells that recognize listeriolysin O. Analysis of epitope-specific CD8+ T cell expansion by MHC class I tetramer staining and ELISPOT revealed no deficiency in either the primary or secondary response to LM infection in PO mice. These results demonstrate that the perforin-independent pathway of antilisterial resistance mediated by CD8+ T cells is generalizable to multiple epitopes. Furthermore, the results show that reduced antilisterial resistance observed with polyclonal PO CD8+ T cells is a consequence of a deficiency in effector function and not a result of suboptimal CD8+ T cell priming.

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    • "Eight-to 10-wk-old female WT BALB/c mice were purchased from the National Cancer Institute (Frederick, MD). BALB/c PKO mice (White et al., 1999) were maintained by brothersister mating. All mice where housed under specific pathogen-free conditions at the University of Iowa (Iowa City, IA) animal care unit and experiments followed approved institutional animal care and use protocols. "
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    ABSTRACT: Disruption of the perforin gene results in primary immunodeficiency and an increased susceptibility to opportunistic pathogens. Perforin-deficient (PKO) mice fail to clear primary lymphocytic choriomeningitis virus (LCMV) Armstrong, resulting in persistent infection and functional exhaustion of virus-specific CD8+ T cells. CD8+ T cell responses to Listeria monocytogenes (LM) challenge within the first week after LCMV infection were diminished in both WT and PKO mice, and correlated with enhanced bacterial clearance. However, bacterial challenge at later time points generated similar CD8 T cell responses in both groups of mice. The phenotype and function of pre-existing LM-specific memory CD8+ T cells were maintained in persistently infected PKO mice. Thus persistent LCMV infection, as a result of perforin deficiency, results in dysfunction of the virus-specific CD8+ T cell response but does not compromise the host's ability to maintain pre-existing memory CD8+ T cells or to generate new memory CD8+ T cell responses against other pathogens.
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    ABSTRACT: In the described experimental approach, we use an attenuated LM strain to evoke LM specific CD8+ T cell responses. In this fashion, we can immunize immunocompromised gene knockout mice, that would succumb to low level infection with virulent LM. We then generate antigen matched, LM-specific CD8+ T cell lines from wild-type and gene knockout mice, and compare their capacity to provide immunity to LM infection in vivo. To date, our results demonstrate that CD8+ T cell-derived IFN-gamma and TNF are not required effector functions. Perforin deficiency has an impact on CD8+ T cell immunity but our studies provide strong evidence for the existence of perforin independent pathways of CD8+ T cell immunity to LM. To assess the potential for redundancy in effector mechanisms, we have generated mice deficient in both perforin and IFN-gamma and are developing mice deficient in perforin and TNF. By removing the major CD8+ T cell effector mechanisms, singly and in combination, we will eventually determine whether immunity to LM can be provided by redundant effector pathways or if novel effector mechanisms exist beyond our current knowledge. The generation of MHC matched, single and double knockout mice, will also aid in continuing studies to analyze the role of these molecules in resistance to in vivo infection.
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