Differential requirements by CD4+ and CD8+ T cells for soluble and membrane TNF in control of

Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Research and Evaluation, US Food and Drug Administration, Rockville, MD 20852, USA.
The Journal of Immunology (Impact Factor: 4.92). 01/2008; 179(11):7709-19. DOI: 10.4049/jimmunol.179.11.7709
Source: PubMed


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 CD44(high) memory T cells and clearance of bacteria were similar, although more IFN-gamma 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-alpha 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.

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Available from: Siobhán C Cowley,
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    • "Our understanding of the relative importance of different T-cell populations is still evolving. Cowley et al102 showed that membrane-bound TNF-α expressed by CD8+ and CD4+ T-cells contributed to control of intracellular replication in macrophages but was essential only for protection mediated by CD8+ T-cells. It was further found that IL-23-mediated stimulation of Th17 cells promoted secretion of IL-17A, which contributed to the Th1 and IL-12 responses against F. tularensis LVS.103 "
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