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

Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2005; 174(11):6993-7005. DOI: 10.4049/jimmunol.174.11.6993
Source: PubMed


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(+)CD62L(high) 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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Available from: Sergio Lira, Aug 13, 2014
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    • "of the injected cells. In the transplant setting, Treg lymph node homing and their ability to traffic to the graft are both required for their protection against graft rejection[26]. In this regard, it was shown that culture of Tregs in the presence of rapamycin maintained their expression of the lymphoid homing receptor, CD62L (S1: 68.1% ± 3.00 vs. Final harvest: 72.0% ± 3.51; P = 0.412), which was not preserved when cells were cultured in the absence of rapamycin; P < 0.0001 (Figure 3H). "
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