The Development of a Th1-Type Response and Resistance to <i>Leishmania major</i> Infection in the Absence of CD40-CD40L Costimulation

Abstract

Abstract CD40-CD40L interactions have been shown to be essential for the production of IL-12 and IFN-γ and control of L. major infection. In contrast, C57BL/6 mice deficient in CD28 develop a dominant Th1-type response and heal infection. In this study, we investigate the effects of a deficiency in both CD40L and CD28 molecules on the immune response and the course of L. major infection. We compared infection in mice genetically lacking CD40L (CD40L−/−), CD28 (CD28−/−), or both (CD40L−/−CD28−/−), and in C57BL/6 mice, all on a resistant background. Although CD40L−/− mice failed to control infection, CD28−/− and CD40L−/−CD28−/− mice, as well as C57BL/6 mice, spontaneously resolved their infections. Healing mice had reduced numbers of lesion parasites compared with nonhealing CD40L−/− mice. At wk 9 of infection, we detected similar levels of IL-4, IFN-γ, IL-12p40, and IL-12Rβ2 mRNA in draining lymph nodes of healing C57BL/6, CD28−/−, and CD40L−/−CD28−/− mice, whereas CD40L−/− mice had increased mRNA levels for IL-4 but reduced levels for IFN-γ, IL-12p40, and IL-12Rβ2. In a separate experiment, blocking of the CD40-CD40L pathway using Ab to CD40L led to an exacerbation of infection in C57BL/6 mice, but had little or no effect on infection in CD28−/− mice. Together, these results demonstrate that in the absence of CD28 costimulation, CD40-CD40L interaction is not required for the development of a protective Th1-type response. The expression of IL-12p40, IL-12Rβ2, and IFN-γ in CD40L−/−CD28−/− mice further suggests the presence of an additional stimulus capable of regulating IL-12 and its receptors in absence of CD40-CD40L interactions.