Interleukin-12p40 mediates transient protection against Mycobacterium avium infection in the absence of interleukin-12

Produced by macrophages and dendritic cells, interleukin (IL)-12 is composed of a p35 and a p40 subunit and promotes protection against intracellular pathogens through the development of interferon-gamma (IFNgamma) -producing T cells. The p40 subunit is also shared by the dimeric cytokines IL-12p40 homodimer and IL-23. In man, genetic defects in IL-12p40-mediated mechanisms are responsible for the familial occurrence of nontuberculous mycobacterial infections, the most common of which is infection with Mycobacterium avium. To experimentally differentiate the contribution of IL-12p40-containing cytokines in the outcome of M. avium infection, we studied wild-type, p35- and p35/p40 doubly deficient mice in an intravenous infection model which reflects many parameters of the disseminated infection in humans. Our study shows that in contrast to p35/p40 doubly deficient mice, p35-deficient mice mount a transient antibacterially protective response against M. avium although such animals were unable to produce detectable levels of IFNgamma or generate efficient granulomas. In conclusion, our results identify an antibacterial effector mechanism preserved in p35-deficient mice that is absent in mice devoid of p35 and p40. This phenotype probably reflects an IL-12p40-dependent effect on macrophage activation at the level of innate immunity.