title: Defects in the generation of IFN-gamma are overcome to control infection with Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage inflammatory protein-1 alpha-, or CCR2-deficient mice.
abstract: We investigated the immune responses in mice lacking CCR2, CCR5, or macrophage inflammatory protein-1 alpha (MIP-1 alpha), a ligand for CCR5, in two situations: following T cell stimulation or after challenge with Leishmania donovani, an intracellular microbe whose control is dependent on a Th1 immune response. Mice deficient in CCR5, MIP-1 alpha, or CCR2 had reduced IFN-gamma responses following ligation of the TCR. Reduced IFN-gamma responses following PMA and ionomycin were also observed in CD8+ T cells of CCR5-/- and CCR2-/- mice. During the early phases of infection, all three knockout mice had low Ag-specific IFN-gamma responses. However, this reduced IFN-gamma response was overcome during a state of persistent Ag stimulation (chronic infection), and was not associated with an adverse parasitologic outcome in any of the gene-targeted mouse strains. To the contrary, during the late phase of infection, an exaggerated Ag-specific IFN-gamma response was evident in CCR5-/- and MIP-1 alpha-/- mice, and this correlated with an enhanced control of parasite replication. Although granuloma formation was abnormal in each of the knockout mice, there was no correlation between the number or architecture of the granulomas and parasite burden. Collectively, these findings indicate an important role for CCR5, MIP-1 alpha, and CCR2 in granulomatous inflammation, and that CCR5 and MIP-1 alpha, possibly acting through CCR5, might play a deleterious role in the outcome of chronic L. donovani infection. Our data also suggest that there might be cross-talk between TCR and chemokine receptor signaling pathways.
authors.affiliation: South Texas Veterans Health Care System, Audie L. Murphy Division, Department of Medicine, University of Texas Health Science Center, San Antonio 78229, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sato
authors.forename: W A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: P C
authors.initials: PC
authors.lastname: Melby
authors.forename: R L
authors.initials: RL
authors.lastname: Reddick
authors.forename: V
authors.initials: V
authors.lastname: Kostecki
authors.forename: W
authors.initials: W
authors.lastname: Zhao
authors.forename: N
authors.initials: N
authors.lastname: Maeda
authors.forename: S K
authors.initials: SK
authors.lastname: Ahuja
authors.forename: S S
authors.initials: SS
authors.lastname: Ahuja
mesh_terms: D000818:Animals; D054407:Chemokine CCL4; D016207:Cytokines / Q000096:biosynthesis; D006099:Granuloma / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency*; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C515335:Ccr2 protein, mouse; D054407:Chemokine CCL4; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D007371:Interferon-gamma