Cc Chemokine Receptor (Ccr)2 Is Required for Langerhans Cell Migration and Localization of T Helper Cell Type 1 (Th1)-Inducing Dendritic Cells

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)-1α, a ligand for CCR5, influence DC migration and localization. We found that deficiency of CCR2 but not CCR5 or MIP-1α 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 CD8α1 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.

Deficiency of Lymph Node-Resident Dendritic Cells (DCs) and Dysregulation of DC Chemoattractants in a Malnourished Mouse Model of Leishmania donovani Infection

“…*, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.001; ****, P Ͻ 0.0001. ments and the localization of the parasite relative to fibroblastic reticular cells (ER-TR7 ϩ ), macrophages (MOMA-2 ϩ ), DCs (CD11c ϩ ), and CD169 ϩ cells at 1 and 3 days postinfection. In prior studies of L. major in CCR2 Ϫ/Ϫ mice, infected cells were localized to the subcapsular sinus of the draining lymph nodes without traversing into the subcortical region (39). In contrast, we found that L. donovani parasites were dispersed throughout the lymph nodes of both CCR2 Ϫ/Ϫ and control mice (Fig.…”

“…We found that malnutrition dysregulated the two principal chemoattractant pathways (CCR7 with its ligands CCL19 and CCL21 and CCR2 with its ligands CCL2 and CCL7) involved in the recruitment of DCs (39,49,51,52). CCR2, in response to CCL2 and CCL7, also regulates the egress of monocytes from the bone marrow to enter the circulation (53-56) and peripheral lymph nodes via high endothelial venules (57)(58)(59).…”

“…In prior studies, Leishmania-infected DCs expressed the CCR7 receptor and migrated in response to its ligand CCL21 (37,38), but DCs from CCR2 Ϫ/Ϫ mice failed to enter the lymph node and accumulated in the subcapsular sinus following cutaneous L. major infection (39). We therefore investigated whether the dysregulated CCR2 and CCR7 mRNA expression in the lymph nodes of the infected malnourished mice was accompanied by altered receptor expression on macrophages and DCs (see the flow cytometry gating protocol in Fig.…”

The CC Chemokine Eotaxin (CCL11) Is a Partial Agonist of CC Chemokine Receptor 2b

“…Since CCR3 is expressed on cells believed to be involved in Th2 responses and CXCR3 in cells characteristic of the Th1 response (42,43), it was postulated by Weng et al (41) that eotaxin may play a role in the impairment of Th1 responses in pathological conditions. Moreover, CCR2 has also been proposed to be characteristic of cells involved in the development of a Th1 response (44,45), and mice null for CCR2 exhibit a Th2 bias (46 -48). In view of the data we present here, we propose that similar to its antagonistic activity at CXCR3, low nanomolar concentrations of eotaxin, as found in inflammatory settings, may be an important modulator of inflammation and Th1/Th2 bias.…”

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

“…CHIKV infections induce a strongly Th1-biased immune response (10,11), with CCR2 Ϫ/Ϫ mice being reported to have impaired Th1 responses (20,40,41). However, analysis of anti-CHIKV IgG2c (Th1) and IgG1 (Th2) titers (32,42) illustrated that the dominant IgG2c responses were not significantly different in CCR2 Ϫ/Ϫ mice (Fig.…”