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The Development of a Th1-Type Response and Resistance to Leishmania major Infection in the Absence of CD40-CD40L Costimulation¹

Udaikumar M. Padigel^*, Peter J. Perrin^2, and Jay P. Farrell^3,*

^* Department of Pathobiology, School of Veterinary Medicine, and Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

CD40-CD40L interactions have been shown to be essential for the production of IL-12 and IFN- 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-, IL-12p40, and IL-12R2 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-, IL-12p40, and IL-12R2. 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-12R2, and IFN- 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.

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