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.