title: Loss of TNF signaling facilitates the development of a novel Ly-6C(low) macrophage population permissive for Leishmania major infection.
abstract: In the absence of TNF, the normally resistant C57BL/6 (B6.WT) strain develops a fatal, progressive form of leishmaniasis after infection with Leishmania major. It is not yet understood which TNF activity or the lack thereof is responsible for the dramatic progression of leishmaniasis in TNF-negative (B6.TNF(-/-)) mice. To elucidate the underlying mechanisms resulting in the fatal outcome of L. major infection in this gene-deficient mouse strain, we analyzed the monocytic component of the inflammatory infiltrate in the draining popliteal lymph node and the site of the infection using multicolor flow cytometry. The leukocytic infiltrate within the draining lymph node and footpad of B6.TNF(-/-) mice resembled that of B6.WT mice over the first 2 wk of cutaneous L. major infection. Thereafter, the B6.TNF(-/-) mice showed an increase of CD11c(+)Ly-6C(+)CCR2(+) monocytic dendritic cells within the popliteal lymph node in comparison with B6.WT mice. This increase of inflammatory dendritic cells was paired with the accumulation of a novel CD11b(+)Ly-6C(low)CCR2(low) population that was not present in B6.WT mice. This B6.TNF(-/-)- and B6.TNFR1(-/-)-specific cell population was CD115(+)Ly-6G(-)iNOS(-), not apoptotic, and harbored large numbers of parasites.
authors.affiliation: ANZAC Research Institute, Concord Hospital, Sydney, New South Wales 2039, Australia.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Fromm
authors.forename: Jessica
authors.initials: J
authors.lastname: Kling
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: Jonathon D
authors.initials: JD
authors.lastname: Sedgwick
authors.forename: Heinrich
authors.initials: H
authors.lastname: Körner
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D018189:Immunomagnetic Separation; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000950:Antigens, Ly; C494192:Ly-6C antigen, mouse; D014409:Tumor Necrosis Factor-alpha