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from Antigen-Specific CD8+ T Cells in Protective Immunity to Listeria monocytogenes1
* Department of Microbiology and
Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242
Whether IFN-
contributes to the per-cell protective capacity of memory CD8+ T cells against Listeria monocytogenes (LM) has not been formally tested. In this study, we generated LM Ag-specific memory CD8+ T cells via immunization of wild-type (WT) and IFN--deficient (gamma knockout (GKO)) mice with LM peptide-coated dendritic cells and compared them phenotypically and functionally. Immunization of WT and GKO mice resulted in memory CD8+ T cells that were similar in number, functional avidity, TCR repertoire use, and memory phenotype. The protective capacity of memory CD8+ T cells from immunized WT and GKO mice was evaluated after adoptive transfer of equal numbers of WT or GKO cells into naive BALB/c mice followed by LM challenge. The adoptively transferred CD8+ T cells from GKO donors exhibited a decreased ability to reduce bacterial numbers in the organs of recipient mice when compared with an equivalent number of Ag-matched WT CD8+ T cells. This deficiency was most evident early (day 3) after infection if a relatively low infectious dose was used; however, transferring fewer memory CD8+ T cells or increasing the LM challenge dose revealed a more pronounced defect in protective immunity mediated by the CD8+ T cells from GKO mice. Our studies identified a decrease in Ag-specific target cell lysis in vivo by CD8+ T cells from GKO mice as the mechanism for the decreased protective immunity after LM challenge. Further studies suggest that the lack of IFN- production by the Ag-specific CD8 T cells themselves diminishes target cell sensitivity to cytolysis, thereby reducing the lytic potency of IFN--deficient LM-specific memory CD8+ T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI42767, AI46653, AI50073, and AI59752 (to J.T.H.), Grant IRG-77-004-28 from the American Cancer Society, administered through The Holden Comprehensive Cancer Center at University of Iowa (to V.P.B.) and an American Cancer Society Postdoctoral Fellowship (to K.A.N.M.).
2 Address correspondence and reprint requests to Dr. John T. Harty, Department of Microbiology, University of Iowa, 3-512 Bowen Science Building, 51 Newton Road, Iowa City, IA 52242. E-mail address: john-harty{at}uiowa.edu
3 Abbreviations used in this paper: KO, knockout; GKO, IFN--deficient KO; LM, Listeria monocytogenes; WT, wild type; DC, dendritic cell; LCMV, lymphocytic choriomeningitis virus; LLO, listeriolysin O; NP, nuclear protein; ICS, intracellular cytokine staining; p.i., postinfection; MFI, mean fluorescence intensity; LOD, limit of detection.
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