Mechanism and localization of CD8 regulatory T cells in a heart transplant model of tolerance.
Despite accumulating evidence for the importance of allospecific CD8(+) regulatory T cells (Tregs) in tolerant rodents and free immunosuppression transplant recipients, mechanisms underlying CD8(+) Treg-mediated tolerance remain unclear. By using a model of transplantation tolerance mediated by CD8(+) Tregs following CD40Ig treatment in rats, in this study, we show that the accumulation of tolerogenic CD8(+) Tregs and plasmacytoid dendritic cells (pDCs) in allograft and spleen but not lymph nodes was associated with tolerance induction in vascularized allograft recipients. pDCs preferentially induced tolerogenic CD8(+) Tregs to suppress CD4(+) effector cells responses to first-donor Ags in vitro. When tolerogenic CD8(+) Tregs were not in contact with CD4(+) effector cells, suppression was mediated by IDO. Contact with CD4(+) effector cells resulted in alternative suppressive mechanisms implicating IFN-gamma and fibroleukin-2. In vivo, both IDO and IFN-gamma were involved in tolerance induction, suggesting that contact with CD4(+) effector cells is crucial to modulate CD8(+) Tregs function in vivo. In conclusion, CD8(+) Tregs and pDCs interactions were necessary for suppression of CD4(+) T cells and involved different mechanisms modulated by the presence of cell contact between CD8(+) Tregs, pDCs, and CD4(+) effector cells.
Li
Xian Liang
XL
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 643, Nantes, France. Lix1@graduate.hku.hk
Ménoret
Séverine
S
Bezie
Séverine
S
Caron
Lise
L
Chabannes
Dominique
D
Hill
Marcelo
M
Halary
Franck
F
Angin
Mathieu
M
Heslan
Michèle
M
Usal
Claire
C
Liang
Liang
L
Guillonneau
Carole
C
Le Mauff
Brigitte
B
Cuturi
Maria Cristina
MC
Josien
Régis
R
Anegon
Ignacio
I
D000256:Adenoviridae / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D016027:Heart Transplantation / Q000276:immunology* / Q000379:methods; D007108:Immune Tolerance / Q000276:immunology*; D008297:Male; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D014161:Transduction, Genetic; D014184:Transplantation, Homologous
C499839:CD40Ig protein, recombinant; D011993:Recombinant Fusion Proteins