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The Journal of Immunology, 2005, 174: 6993-7005.
Copyright © 2005 by The American Association of Immunologists

Lymph Node Occupancy Is Required for the Peripheral Development of Alloantigen-Specific Foxp3+ Regulatory T Cells1

Jordi C. Ochando2,*, Adam C. Yopp*, Yu Yang*, Alexandre Garin{ddagger}, Yansui Li{dagger}, Peter Boros{dagger}, Jaime Llodra*, Yaozhong Ding*,{dagger}, Sergio A. Lira{ddagger}, Nancy R. Krieger3,{dagger} and Jonathan S. Bromberg2,*,{dagger}

* Department of Gene and Cell Medicine, {dagger} Recanati/Miller Transplantation Institute, and {ddagger} Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029

We previously demonstrated that L-selectin (CD62L)-dependent T cell homing to lymph nodes (LN) is required for tolerance induction to alloantigen. To explore the mechanisms of this observation, we analyzed the development and distribution of regulatory T cells (Treg), which play an important protective role against allograft rejection in transplantation tolerance. Alloantigen-specific tolerance was induced using either anti-CD2 plus anti-CD3 mAbs, or anti-CD40L mAbs plus donor-specific transfusion, in fully mismatched (BALB/c donor, C57BL/6 recipient) vascularized cardiac allografts. An expansion of CD4+CD25+CD62Lhigh T cells was observed specifically within the LN of tolerant animals, but not in other anatomic sites or under nontolerizing conditions. These cells exhibited a substantial up-regulation of Foxp3 expression as measured by real-time PCR and by fluorescent immunohistochemistry, and possessed alloantigen-specific suppressor activity. Neither LN nor other lymphoid cells expressed the regulatory phenotype if recipients were treated with anti-CD62L mAbs, which both prevented LN homing and caused early allograft rejection. However, administration of FTY720, a sphingosine 1-phosphate receptor modulator that induces CD62L-independent T cell accumulation in the LNs, restored CD4+CD25+ Treg in the LNs along with graft survival. These data suggest that alloantigen-specific Foxp3+CD4+CD25+ Treg develop and are required within the LNs during tolerization, and provide compelling evidence that distinct lymphoid compartments play critical roles in transplantation tolerance.




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