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

doi:10.1084/jem.192.2.205

Published online 10 July 2000.

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© The Rockefeller University Press, 0022-1007/2000/7/205/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 205-218

Original Article

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

Naoko Sato^a,b, Sunil K. Ahuja^a,b, Marlon Quinones^a,b, Vannessa Kostecki^a,b, Robert L. Reddick^c, Peter C. Melby^a,b, William A. Kuziel^d,e, and Seema S. Ahuja^a,b
^a South Texas Veterans Health Care System, Audie L. Murphy Division,
^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

Correspondence to: Seema S. Ahuja, Department of Medicine (Mail Code 7880), University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel:210-567-4691 Fax:210-567-4654 E-mail:ahuja{at}uthscsa.edu.

There is growing evidence that chemokines and their receptorsregulate the movement and interaction of antigen-presentingcells such as dendritic cells (DCs) and T cells. We tested thehypothesis that the CC chemokine receptor (CCR)2 and CCR5 andthe chemokine macrophage inflammatory protein (MIP)-1 ${alpha}$ , a ligandfor CCR5, influence DC migration and localization. We foundthat deficiency of CCR2 but not CCR5 or MIP-1 ${alpha}$ led to distinctdefects in DC biology. Langerhans cell (skin DC) density inCCR2-null mice was normal, and their ability to migrate intothe dermis was intact; however, their migration to the draininglymph nodes was markedly impaired. CCR2-null mice had lowernumbers of DCs in the spleen, and this was primarily due toa reduction in the CD8 ${alpha}$ ¹ T helper cell type 1 (Th1)-inducingsubset of DCs. Additionally, there was a block in the Leishmaniamajor infection–induced relocalization of splenic DCsfrom the marginal zone to the T cell areas. We propose thatthese DC defects, in conjunction with increased expression ofB lymphocyte chemoattractant, a B cell–specific chemokine,may collectively contribute to the striking B cell outgrowthand Th2 cytokine–biased nonhealing phenotype that we observedin CCR2-deficient mice infected with L. major. This diseasephenotype in mice with an L. major–resistant genetic backgroundbut lacking CCR2 is strikingly reminiscent of that observedtypically in mice with an L. major–susceptible geneticbackground. Thus, CCR2 is an important determinant of not onlyDC migration and localization but also the development of protectivecell-mediated immune responses to L. major.

Key Words: infectious immunity, chemokine, cytokine, knockout, T helpercell

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