title: Differential requirements by CD4+ and CD8+ T cells for soluble and membrane TNF in control of Francisella tularensis live vaccine strain intramacrophage growth.
abstract: 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.
authors.affiliation: Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Research and Evaluation, US Food and Drug Administration, Rockville, MD 20852, USA. siobhan.cowley@fda.hhs.gov
authors.forename: Siobhán C
authors.initials: SC
authors.lastname: Cowley
authors.forename: Jonathon D
authors.initials: JD
authors.lastname: Sedgwick
authors.forename: Karen L
authors.initials: KL
authors.lastname: Elkins
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology; D005604:Francisella tularensis / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis; D012995:Solubility; D048069:Tumor Necrosis Factors / Q000502:physiology*
chemical_list: D001428:Bacterial Vaccines; D048069:Tumor Necrosis Factors; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma