Randolph J. Noelle highlighted by a reduction of organized granuloma formation, that increased appearance of poorly differenti-Department of Microbiology ated macrophages together with reduced ulceration and Dartmouth Medical School necrosis. As found in the study cited above, no gross Lebanon, New Hampshire 03756 changes in T or B cell populations could account for At the onset, it appeared that immunology had finally the altered susceptibility to infection by the parasite. identified a molecule with a singular function in the regu- Reduced IgG and IgE antibody titers to parasite antigens lation of humoral immunity. Early studies in mice and also were noted in the CD40L/ mice. Assessment of mutations in humans (hyper immunoglobulin M syn- T cell function in the CD40L/ mice revealed a lowered drome; HIM) all pointed an accusatory finger at the li- T cell proliferative response to parasite antigens and a gand for CD40 (gp39; CD40L) as the cardinal element virtual absenceof IFNand lymphotoxin–tumor necrosis inthe initiation of humoralimmune responses to thymus- factor production. This was similar to the defect in independent (TD) antigens (reviewed by Durie et al., flammatory cytokines observed in CD40L/ mice in-1994b). However, just as interleukin-2 (IL-2) and IL-4 fected with L. major. Interestingly, attempts to protect have lost their identity as unique T cell and B cell growth mice from infection with vaccination to L. amazonensis proved futile in the CD40L/ mice, yet effective in wildfactors, respectively, so CD40L is losing its identity as type mice. Central to the diminished resistance to L. an effector molecule that is exclusively involved in the amazonensis in the CD40L/ is a reduced capacity of regulation of humoral immunity. A recent flurry of manumacrophages to exert antiparasitic responses such as scripts underscore the importance of this ligand–nitric oxide (NO) production. However, unlike the studies receptor pair in host defense outside of its central funccited above, studies with L. amazonensis showed that tion in the regulation of humoral immunity. the production of IL-12 was comparable to wild-type mice. This lead the authors to conclude that the major Cell-Mediated Immunity contributing defect to increased susceptibility to L. ama-CD40 and Immunity to Microbes zonensis infection was diminished macrophage activa-Using mice whose CD40L or CD40 gene was disrupted tion and NO production. by homologous recombination, three reports have re- Early studies describing the defects in CD40L/ and cently established that CD40L is required for protective CD40/ mice revealed that disruption of either the recell-mediated immunity to Leishmania major and to ceptor or the ligand or, in fact, treatment of mice with Leishmania amazonensis (Campbell et al., 1996; Kama- a neutralizing anti-CD40L antibody, resulted in identical naka et al., 1996; Soong et al., 1996). In the CD40L- phenotypic changes in the humoral immune response. defective mice backbred onto a genetic background Similarly, it has been reported (Kamanaka et al., 1996) normally resistant to progressive infection with L. major, that CD40-deficient mice, like the CD40L-deficient mice, the acquisition of a susceptible phenotype was ob- have an increased susceptibility to L. major, and cannot served (Campbell et al., 1996). The evaluation of the T resolve the infection. As observed in the CD40L/ mice cell priming in these mice showed that the T cells from infected with L. major, the CD40/ mice produced lowthe wild-type infected mice produced 100-to 150-fold ered amounts of IFN and IL-12. In the CD40/ mice, more interferon (IFN) then T cells from CD40L/ mice. higher levels of …