title: CC chemokine receptor (CCR)2 is required for langerhans cell migration and localization of T helper cell type 1 (Th1)-inducing dendritic cells. Absence of CCR2 shifts the Leishmania major-resistant phenotype to a susceptible state dominated by Th2 cytokines, b cell outgrowth, and sustained neutrophilic inflammation.
abstract: There is growing evidence that chemokines and their receptors regulate the movement and interaction of antigen-presenting cells such as dendritic cells (DCs) and T cells. We tested the hypothesis that the CC chemokine receptor (CCR)2 and CCR5 and the chemokine macrophage inflammatory protein (MIP)-1alpha, a ligand for CCR5, influence DC migration and localization. We found that deficiency of CCR2 but not CCR5 or MIP-1alpha led to distinct defects in DC biology. Langerhans cell (skin DC) density in CCR2-null mice was normal, and their ability to migrate into the dermis was intact; however, their migration to the draining lymph nodes was markedly impaired. CCR2-null mice had lower numbers of DCs in the spleen, and this was primarily due to a reduction in the CD8alpha(1) T helper cell type 1 (Th1)-inducing subset of DCs. Additionally, there was a block in the Leishmania major infection-induced relocalization of splenic DCs from the marginal zone to the T cell areas. We propose that these DC defects, in conjunction with increased expression of B lymphocyte chemoattractant, a B cell-specific chemokine, may collectively contribute to the striking B cell outgrowth and Th2 cytokine-biased nonhealing phenotype that we observed in CCR2-deficient mice infected with L. major. This disease phenotype in mice with an L. major-resistant genetic background but lacking CCR2 is strikingly reminiscent of that observed typically in mice with an L. major-susceptible genetic background. Thus, CCR2 is an important determinant of not only DC migration and localization but also the development of protective cell-mediated immune responses to L. major.
authors.affiliation: South Texas Veterans Health Care System, Audie L. Murphy Division, Austin, 78712-1095, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sato
authors.forename: S K
authors.initials: SK
authors.lastname: Ahuja
authors.forename: M
authors.initials: M
authors.lastname: Quinones
authors.forename: V
authors.initials: V
authors.lastname: Kostecki
authors.forename: R L
authors.initials: RL
authors.lastname: Reddick
authors.forename: P C
authors.initials: PC
authors.lastname: Melby
authors.forename: W A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: S S
authors.initials: SS
authors.lastname: Ahuja
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002465:Cell Movement; D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology*; D007801:Langerhans Cells / Q000502:physiology*; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000502:physiology; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000502:physiology*; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*
chemical_list: C515335:Ccr2 protein, mouse; D054382:Chemokine CXCL13; D019743:Chemokines, CXC; C486386:Cxcl13 protein, mouse; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine