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* Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Research and Evaluation, U.S. Food and Drug Administration, Rockville, MD 20852; and
Eli Lilly and Company, Indianapolis, IN 46285
During primary infection with intracellular bacteria, the membrane-associated form of TNF provides some TNF functions, but the relative contributions during memory responses are not well-characterized. In this study, we determined the role of T cell-derived secreted and membrane-bound TNF (memTNF) during adaptive immunity to Francisella tularensis live vaccine strain (LVS). Although transgenic mice expressing only the memTNF were more susceptible to primary LVS infection than wild-type (WT) mice, LVS-immune WT and memTNF mice both survived maximal lethal secondary Francisella challenge. Generation of CD44high memory T cells and clearance of bacteria were similar, although more IFN-
and IL-12(p40) were produced by memTNF mice. To examine T cell function, we used an in vitro tissue coculture system that measures control of LVS intramacrophage growth by LVS-immune WT and memTNF-T cells. LVS-immune CD4+ and CD8+ T cells isolated from WT and memTNF mice exhibited comparable control of LVS growth in either normal or TNF-
knockout macrophages. Although the magnitude of CD4+ T cell-induced macrophage NO production clearly depended on TNF, control of LVS growth by both CD4+ and CD8+ T cells did not correlate with levels of nitrite. Importantly, intramacrophage LVS growth control by CD8+ T cells, but not CD4+ T cells, was almost entirely dependent on T cell-expressed TNF, and required stimulation through macrophage TNFRs. Collectively, these data demonstrate that T cell-expressed memTNF is necessary and sufficient for memory T cell responses to this intracellular pathogen, and is particularly important for intramacrophage control of bacterial growth by 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 Address correspondence and reprint requests to Dr. Siobhán C. Cowley, or Dr. Karen L. Elkins, Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Research and Evaluation, U.S. Food and Drug Administration, 1401 Rockville Pike, HFM 431, Rockville, MD 20852; E-mail addresses: siobhan.cowley{at}fda.hhs.gov and karen.elkins{at}fda.hhs.gov
2 Abbreviations used in this paper: LVS, live vaccine strain; i.d., intradermal; memTNF, membrane-bound TNF; WT, wild type; KO, knockout; BMM
, bone marrow-derived macrophage; cDMEM, complete DMEM.
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