The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/1/265/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 2, January 17, 2000 265-274

Original Article

Cc Chemokine Receptor (Ccr)3/Eotaxin Is Followed by Ccr4/Monocyte-Derived Chemokine in Mediating Pulmonary T Helper Lymphocyte Type 2 Recruitment after Serial Antigen Challenge in Vivo

Clare M. Lloyda, Tracy Delaneya, Trang Nguyena, Jane Tiana, Carlos Martinez-Ab, Anthony J. Coylea, and Jose-Carlos Gutierrez-Ramosa

a Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139
b Department of Immunology and Oncology, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cientificas, Universidad Autonoma, Centroblanco, E28049 Madrid, Spain
Millennium Pharmaceuticals, Inc., 45 Sidney St., Cambridge, MA 02139.617-551-8910617-679-7262

gutierrez{at}mpi.com

Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises when the in vivo significance of this distinct expression is discussed. To address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo recruitment of Th2 cells, we have transferred effector Th cells into naive mice to induce allergic airway disease. Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells. We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.

Key Words: chemokines • effector T helper type 2 cells • migration • allergic airway disease • chemokine receptors

Abbreviations used in this paper: AAD, allergic airway disease; BAL, bronchoalveolar lavage; BHR, bronchial hyperresponsiveness; CCR, CC chemokine receptor; hpf, high-power field(s); MDC, monocyte-derived chemokine; Penh, enhanced pause; TARC, thymus and activation-regulated chemokine.

© 2000 The Rockefeller University Press


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