The Journal of Experimental Medicine
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Published 4 April 2005. doi:10.1084/jem.20041709
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 7, 1037-1044
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BRIEF DEFINITIVE REPORT

 Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor

Iris Lee1, Liqing Wang1, Andrew D. Wells1, Martin E. Dorf2, Engin Ozkaynak3, and Wayne W. Hancock1

1 Department of Pathology and Laboratory Medicine, Joseph Stokes Jr. Research Institute and Biesecker Pediatric Liver Center, The Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104
2 Department of Pathology, Harvard Medical School, Boston, MA 02115
3 TolerRx, Inc., Cambridge, MA 02139

CORRESPONDENCE Wayne W. Hancock: whancock{at}mail.med.upenn.edu

Although certain chemokines and their receptors guide homeostatic recirculation of T cells and others promote recruitment of activated T cells to inflammatory sites, little is known of the mechanisms underlying a third function, migration of Foxp3+ regulatory T (T reg) cells to sites where they maintain unresponsiveness. We studied how T reg cells are recruited to cardiac allografts in recipients tolerized with CD154 monoclonal antibody (mAb) plus donor-specific transfusion (DST). Real-time polymerase chain reaction showed that intragraft Foxp3 levels in tolerized recipients were ~100-fold higher than rejecting allografts or allografts associated with other therapies inducing prolonged survival but not tolerance. Foxp3+ cells were essential for tolerance because pretransplant thymectomy or peritransplant depletion of CD25+ cells prevented long-term survival, as did CD25 mAb therapy in well-functioning allografts after CD154/DST therapy. Analysis of multiple chemokine pathways showed that tolerance was accompanied by intragraft up-regulation of CCR4 and one of its ligands, macrophage-derived chemokine (CCL22), and that tolerance induction could not be achieved in CCR4–/– recipients. We conclude that Foxp3 expression is specifically up-regulated within allografts of mice displaying donor-specific tolerance, that recruitment of Foxp3-expressing T reg cells to an allograft tissue is dependent on the chemokine receptor, CCR4, and that, in the absence of such recruitment, tolerizing strategies such as CD154 mAb therapy are ineffectual.


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