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Original Article |
b Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7880
c Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7880
d Section of Molecular Genetics and Microbiology, University of Texas, Austin, Texas 78712-1095
e Institute of Cellular and Molecular Biology, University of Texas, Austin, Texas 78712-1095
Department of Medicine (Mail Code 7880), University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900.210-567-4654210-567-4691
ahuja{at}uthscsa.edu
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)-1
, a ligand for CCR5, influence DC migration and localization. We found that deficiency of CCR2 but not CCR5 or MIP-1 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 CD81 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.
Key Words: infectious immunity • chemokine • cytokine • knockout • T helper cell
N. Sato and S.K. Ahuja contributed equally to this work.
© 2000 The Rockefeller University Press
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