Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells

Jordi C. Ochando, Adam C. Yopp, Yu Yang, Alexandre Garin, Yansui Li, Peter Boros, Jaime Llodra, Yaozhong Ding, Sergio A. Lira, Nancy R. Krieger, Jonathan S. Bromberg

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)6993-7005
Number of pages13
JournalJournal of Immunology
Volume174
Issue number11
DOIs
StatePublished - Jun 1 2005

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Ochando, J. C., Yopp, A. C., Yang, Y., Garin, A., Li, Y., Boros, P., Llodra, J., Ding, Y., Lira, S. A., Krieger, N. R., & Bromberg, J. S. (2005). Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells. Journal of Immunology, 174(11), 6993-7005. https://doi.org/10.4049/jimmunol.174.11.6993