The Development of a Th1-Type Response and Resistance toLeishmania majorInfection in the Absence of CD40-CD40L Costimulation

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.

TRANCE-RANK Costimulation is Required for IL-12 Production and the Initiation of a Th1-Type Response toLeishmania majorInfection in CD40L-Deficient Mice

“…However, these studies used a high parasite dose and we have shown that the ability to heal may be directly related to the parasite dose used to initiate infection. Thus, we observed that mice inoculated with 1 ϫ 10 6 promastigotes developed progressive disease, whereas mice inoculated with 2 ϫ 10 4 promastigotes resolved their infections (25). We also showed that healing CD40L deficient mice have numbers of IL-12 producing cells similar to those in control mice suggesting that an alternate pathway of IL-12 production may operate in the absence of CD40-CD40L costimulation (26).…”

“…The basis of this current study is our previous observation that CD40L Ϫ/Ϫ mice can control L. major infection and develop a dominant Th1 response following inoculation of a reduced number of parasites (25). Thus, an alternate pathway other than CD40-CD40L costimulation must be used in these mice to promote IL-12 production.…”

“…It is logical to conclude from these studies that the interaction of host APCs with CD40L expressing T cells is critical to the production of IL-12 and activation of a protective Th1 effector cells. However, we have recently shown that CD40-CD40L costimulatory pathway of IL-12 production is not always required for the development of a protective Th1 response since CD40L Ϫ/Ϫ mice, when inoculated with reduced numbers of L. major promastigotes, can resolve a primary infection (25,26). Thus, an alternate pathway for IL-12 production must be used in these healing CD40L Ϫ/Ϫ mice.…”

Interaction of Macrophage Antigen 1 and CD40 Ligand Leads to IL-12 Production and Resistance in CD40-Deficient Mice Infected with Leishmania major

“…Although some studies show that CD40-CD40L interaction is critical for IL-12 and the development of protective anti-Leishmania immunity (7), others show that CD40L-deficient mice are capable of producing IL-12 and mounting a protective Th1 response against L. major infection (8,9). To fully determine the role of CD40 and CD40L in IL-12…”

Antigenic dietary protein guides maturation of the host immune system promoting resistance to Leishmania major infection in C57BL/6 mice

“…Susceptibility to L. major infection has been linked to a deficiency in the engagement between CD40 and CD40L. 8,[38][39][40][41][42][43][44] Furthermore, B7-mediated costimulation is required for the development of the early immune response following infection of either resistant or susceptible mice. 45 Therefore, activation and maturation of APCs with expression of MHC molecules, CD40 and CD80 on the surface of APCs is fundamental to the process of costimulation of T cells for an efficient response to L. major infection.…”