title: Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells.
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(+)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.
authors.affiliation: Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. jordi.ochando@mssm.edu
authors.forename: Jordi C
authors.initials: JC
authors.lastname: Ochando
authors.forename: Adam C
authors.initials: AC
authors.lastname: Yopp
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.forename: Alexandre
authors.initials: A
authors.lastname: Garin
authors.forename: Yansui
authors.initials: Y
authors.lastname: Li
authors.forename: Peter
authors.initials: P
authors.lastname: Boros
authors.forename: Jaime
authors.initials: J
authors.lastname: Llodra
authors.forename: Yaozhong
authors.initials: Y
authors.lastname: Ding
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Krieger
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bromberg
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D003326:Coronary Circulation / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D051858:Forkhead Transcription Factors; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D016130:Immunophenotyping; D007519:Isoantigens / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors; D023001:Transplantation Tolerance / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007519:Isoantigens; D015375:Receptors, Interleukin-2; D016201:Receptors, Lymphocyte Homing; D014157:Transcription Factors