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Fatal Recall Responses Mediated by CD8 T cells during Intracellular Bacterial Challenge Infection¹

Constantine Bitsaktsis^* and Gary Winslow^2,*,

^* Wadsworth Center, New York State Department of Health, Albany, NY 12201; and Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, NY 12201

The roles(s) of CD8 T cells during infections by intracellular bacteria that reside in host cell endocytic compartments are not well understood. Our previous studies in a mouse model of human monocytotropic ehrlichiosis indicated that CD8 T cells are not essential for immunity. However, we have observed an unexpected role for these cells during challenge infection. Although immunocompetent mice cleared a primary low-dose (nonfatal) Ixodes ovatus ehrlichia infection, a secondary low-dose challenge infection resulted in fatal disease and loss of control of infection. The outcome was CD8-dependent, because CD8-deficient mice survived secondary low-dose challenge infection. Moreover, effector and/or memory phenotype CD8 T cells were responsible, because adoptive transfer of purified CD44^high CD8 T cells to naive mice induced fatal responses following a primary low-dose infection. The fatal responses were perforin- and Fas ligand-independent, and were associated with high serum concentrations of TNF- and CCL2, and low levels of IL-10. Accordingly, blockade of either TNF- or CCL2 ameliorated fatal recall responses, and in vitro coculture of memory CD8 T cells and Ixodes ovatus ehrlichia-infected peritoneal exudate cells resulted in substantial increases in TNF- and CCL2. Thus, during monocytotropic ehrlichiosis, inflammatory cytokine production, by CD8 T cells and/or other host cells, can trigger chemokine-dependent disease. These findings highlight a novel role for CD8 T cells, and reveal that live vaccines for intracellular bacteria can, under some conditions, induce undesirable consequences.

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 U.S. Public Health Service Grant R01AI47963.

² Address correspondence and reprint requests to Dr. Gary Winslow, Wadsworth Center, 120 New Scotland Avenue, Albany, NY 12208. E-mail: gary.winslow{at}wadsworth.org

³ Abbreviations used in this paper: IOE, Ixodes ovatus ehrlichia; ₂m, ₂-microglobulin; FasL, Fas ligand; QPCR, quantitative PCR; CBA, cytometric bead array; PEC, peritoneal exudate cell; KO, knockout.

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