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Infection and Immunity, September 1998, p. 4143-4150, Vol. 66, No. 9
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Fas (CD95)-Dependent Cell-Mediated Immunity to Listeria monocytogenes

Eric R. Jensen,1 Alison A. Glass,2,dagger William R. Clark,2,3,Dagger Edward J. Wing,4,§ Jeff F. Miller,1,3,* and Stephen H. Gregory4

Departments of Microbiology and Immunology1 and Biology2 and Molecular Biology Institute,3 University of California at Los Angeles, Los Angeles, California 90095, and Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 152134

Received 27 March 1998/Returned for modification 6 May 1998/Accepted 4 June 1998

Two distinct and complementary pathways, one mediated by perforin and the other dependent upon CD95 (Fas), effect cell-mediated cytotoxicity. We examined the relative roles of these pathways in host defenses against the intracellular bacterial pathogen Listeria monocytogenes by using murine listeriosis as a model system. Mice which lacked both perforin and Fas (P0L0) were generated, and their responses to primary and secondary listeriosis were compared to those of wild-type (WT), Fas-deficient (L0), and perforin knockout (P0) mice. Relative to WT mice during primary listeriosis, P0 mice exhibited a reduced capacity to clear the infection from their spleens but not their livers whereas L0 mice had elevated bacterial titers in their livers and a modestly increased titer in their spleens. In contrast, bacterial titers in P0L0 mice were increased approximately 50- to 560-fold in their spleens and 230- to 1,000-fold in their livers; eventual clearance of listeriae from both organs was significantly delayed. Furthermore, the resistance of P0L0 mice to secondary listeriosis was significantly reduced in their spleens and livers compared to that of WT, P0, or L0 mice. In vitro experiments indicated that immune cytotoxic T lymphocytes (CTL) lysed L. monocytogenes-infected hepatocytes primarily via a Fas-dependent, perforin-independent mechanism. The absence of Fas severely abrogated the lysis of infected hepatocytes by immune CD8+ CTL. Taken together, these results provide the first evidence for Fas-dependent CTL-mediated lysis of L. monocytogenes-infected hepatocytes and demonstrate complementary roles for Fas and perforin in host defenses against an intracellular bacterial pathogen.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, UCLA School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095-1747. Phone: (310) 206-7926. Fax: (310) 206-3865. E-mail: jfmiller{at}ucla.edu.

dagger Present address: La Jolla Institute of Allergy and Immunology, San Diego, CA 92121.

Dagger Present address: Le Struel, 46270 Prendeignes, France.

§ Present address: Department of Medicine, Rhode Island Hospital, Providence, RI 02903.

Infection and Immunity, September 1998, p. 4143-4150, Vol. 66, No. 9
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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