CC chemokine receptor (CCR)2 is required for Langerhans cell migration andlocalization of T helper cell type 1 (Th1)-inducing dendritic cells: Absence of CCR2 shifts the Leishmania major-resistant phenotype to a susceptiblestate dominated by Th2 cytokines, B cell outgrowth, and sustained neutrophilic inflammation

There is growing evidence that chemokines and their receptors regulate the movement and interaction of antigen-presenting cells such as dendritic cell s (DCs) and T cells. We tested the hy pothesis that the CC chemokine recept or (CCR)2 and CCR5 and the chemokine macrophage inflammatory protein (MIP)- 1 alpha, a ligand for CCR5, influence DC migration and localization. We fou nd that deficiency of CCR2 but not CCR5 or MIP-1 alpha led to distinct defe cts 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, t heir 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 CD8 alpha(+) 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 expr ession of B lymphocyte chemoattractant, a B cell-specific chemokine, may co llectively contribute to the striking B cell outgrowth and Th2 cytokine-bia sed nonhealing phenotype that we observed in CCR2-deficient mice infected w ith L. major. This disease phenotype in mice with an L. major-resistant gen etic background but lacking CCR2 is strikingly reminiscent of that observed typically in mice with an L. major-susceptible genetic background. Thus, C CR2 is an important determinant of not only DC migration and localization b ut also the development of protective cell-mediated immune responses to L. major.