Interleukin-12 in murine leishmaniasis — match, flame or fuel?

• Published in: Research in immunology (Paris) Vol. 146; no. 7; pp. 566 - 575
• Main Authors: Fowell, D.J., Wakil, A.E., Locksley, R.M.
• Format: Journal Article
• Language: English
• Published: France Elsevier B.V 01-09-1995
• Subjects: Animals; Interleukin-12 - physiology; Leishmania major; Leishmania major - immunology; Leishmaniasis, Cutaneous - etiology; Leishmaniasis, Cutaneous - immunology; Mice
• ISSN: 0923-2494
• DOI: 10.1016/0923-2494(96)83033-1

The murine model of Leishmania major infection has proven particularly robust in delineating the role of CD4 super(+) subset maturation in vivo. Effector CD4 super(+) T cells of the Th1 type are required to establish control of infection by the intramacrophage parasites, as demonstrated by the fatal course of disease in T-cell-deficient or MHC class II-deficient (and thus CD4-deficient) mice. Th1 cells are necessary for the production of optimal amounts of IFN gamma , required to stimulate macrophage-inducible nitric oxide synthase (iNOS) and the production of NO that is ultimately capable of restricting parasite replication. Thus, IFN gamma and IFN gamma R knockout as well as iNOS knockout mice, are exquisitely sensitive to infection with L. major. Although almost all inbred mice strains restrict L. major infection through the development of Th1 cells, BALB mice constitute informative failures to this established paradigm. In contrast to other strains, mice on a BALB background aberrantly establish IL4-dominated Th2 responses to L. major, resulting in inefficient macrophage activation and ultimately, a fatal outcome. Interest in the model has focused from its early days on the demonstration that interventions given close to the time of infection were capable of redirecting the aberrant immune response in BALB/c mice, thus enabling these animals to establish effective immunity through the development of parasite-specific Th1 cells. These interventions each shared the ability to make IL4 rate-limiting during the period of T-cell priming, confirming the critical role for this cytokine in Th2 lineage development as established in various in vitro and in vivo systems. The identification of IL12 as the major cytokine responsible for optimizing the production of IFN gamma from both NK cells and T cells generated substantial enthusiasm for understanding the earliest components of the immune response to Leishmania. Direct induction of IL12 from macrophages by Listeria was used to link the innate and adaptive immune responses in coordinating productive cell-mediated immunity, including the maturation of Th1 effectors. The uniform requirement for Th1 cell development in L. major infection suggested that IL12 might prove to be one of the earliest signals generated by macrophages in directing the appropriate cascade of signals required for an effective immune response, and further, that defects in IL12 production might underlie the genetic susceptibility of BALB mice.