In experimental leishmaniasis deficiency of CD18 results in parasite dissemination associated with altered macrophage functions and incomplete Th1 cell response.

We investigated experimental leishmaniasis in CD18-deficient mice. Whereas wild-type (WT) CD18-/- mice (129SV/C57BL/6) were resistant to infection, CD18-/- mice revealed increasing visceral dissemination of parasites. Unlike in other susceptible strains, infected footpads of CD18-/- mice did not ulcerate, due to an abolished recruitment of granulocytes. In vitro, CD18-/- macrophages were able to phagocytose opsonized Leishmania major despite absence of CR3, albeit phagocytosis rate was 50% lower than in WT macrophages. We found that uptake was partially mediated by scavenger receptors. As infected CD18-/- macrophages showed impaired ability to produce NO and to eliminate parasites, CD18 is one mediator of NO production. CD18 is also involved in reduction of IL-12 release by L. major-infected macrophages, as uptake of opsonized parasites (via CR3) decreased IL-12 release only in WT, but not in CD18-/- macrophages. When T cells from infected CD18-/- mice were restimulated with antigen-presenting cells (APC), they released no IL-2 or IL-4, but a little IFN-gamma, associated with lack of proliferation. This deficiency was linked to absence of CD18 on T cells, but not on APC. Substitution with IL-2 specifically restored a Th1-like response with proliferation and release of IFN-gamma. Thus, while impaired phagocytosis, NO production, and recruitment of granulocytes in CD18-/- mice may not reverse resistance, and while unrestricted IL-12 release supports development of Th1 cells, the failure of T cells to release IL-2 and to proliferate causes susceptibility.