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

Research output: Contribution to journalArticle

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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
StatePublished - Jun 1 2005

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Isoantigens
Regulatory T-Lymphocytes
Lymph Nodes
Allografts
Transplantation Tolerance
T-Lymphocytes
Lysosphingolipid Receptors
L-Selectin
CD40 Ligand
Graft Survival
Real-Time Polymerase Chain Reaction
Up-Regulation
Immunohistochemistry
Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Ochando, J. C., Yopp, A. C., Yang, Y., Garin, A., Li, Y., Boros, P., ... 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.

Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells. / Ochando, Jordi C.; Yopp, Adam C.; Yang, Yu; Garin, Alexandre; Li, Yansui; Boros, Peter; Llodra, Jaime; Ding, Yaozhong; Lira, Sergio A.; Krieger, Nancy R.; Bromberg, Jonathan S.

In: Journal of Immunology, Vol. 174, No. 11, 01.06.2005, p. 6993-7005.

Research output: Contribution to journalArticle

Ochando, JC, Yopp, AC, Yang, Y, Garin, A, Li, Y, Boros, P, Llodra, J, Ding, Y, Lira, SA, Krieger, NR & Bromberg, JS 2005, 'Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells', Journal of Immunology, vol. 174, no. 11, pp. 6993-7005.
Ochando, Jordi C. ; Yopp, Adam C. ; Yang, Yu ; Garin, Alexandre ; Li, Yansui ; Boros, Peter ; Llodra, Jaime ; Ding, Yaozhong ; Lira, Sergio A. ; Krieger, Nancy R. ; Bromberg, Jonathan S. / Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells. In: Journal of Immunology. 2005 ; Vol. 174, No. 11. pp. 6993-7005.
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AU - Garin, Alexandre

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AU - Boros, Peter

AU - Llodra, Jaime

AU - Ding, Yaozhong

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AU - Bromberg, Jonathan S.

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