title: In vivo clearance of an intracellular bacterium, Francisella tularensis LVS, is dependent on the p40 subunit of interleukin-12 (IL-12) but not on IL-12 p70.
abstract: To determine the role of interleukin-12 (IL-12) in primary and secondary immunity to a model intracellular bacterium, we have comprehensively evaluated infection with Francisella tularensis LVS in three murine models of IL-12 deficiency. Mice lacking the p40 protein of IL-12 (p40 knockout [KO] mice) and mice treated in vivo with neutralizing anti-IL-12 antibodies survived large doses of primary and secondary LVS infection but never cleared bacteria and exhibited a chronic infection. In dramatic contrast, mice lacking the p35 protein (p35 KO mice) of heterodimeric IL-12 readily survived large doses of primary sublethal LVS infection as well as maximal secondary lethal challenge, with only a slight delay in clearance of bacteria. LVS-immune wild-type (WT) lymphocytes produced large amounts of gamma interferon (IFN-gamma), but p35 KO and p40 KO lymphocytes produced much less; nonetheless, similar amounts of NO were found in all cultures containing immune lymphocytes, and all immune lymphocytes were equally capable of controlling intracellular growth of LVS in vitro. Purified CD4(+) and CD8(+) T cells from both WT and p40 KO mice controlled intracellular growth, even though T cells from WT mice produced much more IFN-gamma than those from p40 KO mice, and p40 KO T cells did not adopt a Th2 phenotype. Thus, while IL-12 p70 stimulation of IFN-gamma production may be important for bacteriostasis, IL-12 p70 is not necessary for appropriate development of LVS-immune T cells that are capable of controlling intracellular bacterial growth and for clearance of primary or secondary LVS infection. Instead, an additional mechanism dependent on the IL-12 p40 protein, either alone or in another complex such as the newly discovered heterodimer IL-23, appears to be responsible for actual clearance of this intracellular bacterium.
authors.affiliation: Laboratory of Mycobacteria, Division of Bacterial, Parasitic, and Allergenic Products, CBER/FDA, Rockville, Maryland 20852, USA. elkins@cber.fda.gov
authors.forename: Karen L
authors.initials: KL
authors.lastname: Elkins
authors.forename: Allison
authors.initials: A
authors.lastname: Cooper
authors.forename: Susan M
authors.initials: SM
authors.lastname: Colombini
authors.forename: Siobhán C
authors.initials: SC
authors.lastname: Cowley
authors.forename: Tara L
authors.initials: TL
authors.lastname: Kieffer
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D005604:Francisella tularensis / Q000276:immunology*; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology*; D053762:Interleukin-12 Subunit p40; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology; D021122:Protein Subunits; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma