The development of a Th1-type response and resistance to Leishmania major infection in the absence of CD40-CD40L costimulation

CD40-CD40L interactions have been shown to be essential for the production of IL-12 and IFN-gamma and control of L. major infection. in contrast, C57B L/6 mice deficient in CD28 develop a dominant Th1-type response and heal in fection. 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 i nfection. We compared infection in mice genetically lacking CD40L (CD40L(-/ -)), CD28 (CD28(-/-)), or both (CD40L(-/-)CD28(-/-)), Ind in C57BL/6 mice, all on a resistant background. Although CD40L-/- mice failed to control inf ection, CD28(-/-) and CD40L(-/-)CD28(-/-) mice, as well as C57BL/6 mice, sp ontaneously resolved their infections. Healing mice had reduced numbers of lesion parasites compared with nonhealing CD40L-/- mice. At wk 9 of infecti on, we detected similar levels of IL-4, IFN-gamma, IL-12p40, and IL-12R bet a2 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-gamma, IL-12p40, and IL-12R beta2. 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 t he development of a protective Th1-type response. The expression of IL-12p4 0, IL-12R beta2, and IFN-gamma 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.