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.
Schönlau
F
F
Department of Experimental Dermatology, University of Münster, Germany.
Scharffetter-Kochanek
K
K
Grabbe
S
S
Pietz
B
B
Sorg
C
C
Sunderkötter
C
C
D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis; D018320:Leishmania major / Q000276:immunology*; D007896:Leishmaniasis / Q000276:immunology*; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000096:biosynthesis; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology; D010587:Phagocytosis; D018417:Th1 Cells / Q000502:physiology*
D018821:CD18 Antigens; D008222:Lymphokines; D018664:Interleukin-12; D009569:Nitric Oxide