Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor.
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 approximately 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.
Lee
Iris
I
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, USA.
Wang
Liqing
L
Wells
Andrew D
AD
Dorf
Martin E
ME
Ozkaynak
Engin
E
Hancock
Wayne W
WW
D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000276:immunology*; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D016027:Heart Transplantation / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D008815:Mice, Inbred Strains; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*; D015854:Up-Regulation
C515483:Ccl22 protein, mouse; C515355:Ccr4 protein, mouse; D054422:Chemokine CCL22; D019742:Chemokines, CC; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D054398:Receptors, CCR4; D019707:Receptors, Chemokine