Alloantigen specific CD8+CD28- FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity.
Endothelial cells have been shown to activate T cell responses to alloantigens, triggering transplant rejection. However, they may also play a role in tolerance induction. Using RT-PCR we show here that alloantigen specific CD8(+)CD28(-) T suppressor cells generated in vitro are FOXP3 positive and interact with human endothelial cells. This interaction results in the induction of inhibitory receptors and down-regulation of costimulatory and adhesion molecules, thus rendering endothelial cells tolerogenic. In turn, tolerized endothelial cells elicit the differentiation of CD8(+)CD28(-) FOXP3(+) T suppressor cells. Taken together our data demonstrate a functional and phenotypic overlap between tolerogenic dendritic cells and endothelial cells. Furthermore, alloantigen specific CD8(+)CD28(-) FOXP3(+) T cells, which trigger the upregulation of inhibitory receptors in endothelial cells, are present in the circulation of heart allograft recipients in quiescence as demonstrated by flow cytometry, RT-PCR and luciferase transcription assays. Their detection facilitates the identification of patients who may benefit from partial or complete cessation of immunosuppressive therapy, a goal of obvious importance given the morbidity and mortality associated with chronic immunosuppression. Modulation of endothelial cells in favor of promoting tolerance may be important for long-term survival of organ allografts.
Manavalan
John S
JS
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Kim-Schulze
Seunghee
S
Scotto
Luigi
L
Naiyer
Afzal J
AJ
Vlad
George
G
Colombo
Paolo C
PC
Marboe
Charles
C
Mancini
Donna
D
Cortesini
Raffaello
R
Suciu-Foca
Nicole
N
D000328:Adult; D001483:Base Sequence; D018106:CD28 Antigens / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology*; D005260:Female; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy / Q000401:mortality; D007519:Isoantigens / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology*
D018106:CD28 Antigens; D007519:Isoantigens; C491341:LILRB2 protein, human; C107907:LILRB4 protein, human; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic