Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells.
Graft-versus-host disease (GVHD) represents one of the major complications of allogeneic hematopoietic stem cell transplantation. Techniques to prevent GVHD have included ex vivo T-cell depletion of the graft or prolonged in vivo immunosuppression. Both reduce the frequency and severity of GVHD but also reduce T-cell-mediated graft-versus-malignancy effect, and increase the risk of infection. A major goal in transplantation is to prevent alloreactivity while preserving activity against tumors and infectious agents. We have used activation of the Notch pathway to try to generate T cells able to specifically regulate alloantigen responses. We used allogeneic Epstein-Barr virus lymphoblastoid B cells (EBV-LCLs) as stimulator cells. Such LCLs are excellent (allo) antigen-presenting cells and can be obtained in large numbers even from donors who have received extensive chemo/radiotherapy. We overexpressed a Notch ligand, Jagged-1, in these cells by adenoviral vector transduction. Stimulation of CD45RA+ naive T cells by Jagged-1 EBV-LCL reduces production of interferon-gamma, interleukin-2, and interleukin-5, but up-regulates transforming growth factor-beta 1 synthesis, consistent with induction of a regulatory T-cell phenotype. Transfer of these T cells to fresh lymphocyte cultures inhibits proliferative and cytotoxic immune responses to the priming alloantigens while sparing responses to third-party stimulator cells. Notch activation in the presence of alloantigen-presenting cells may therefore be a means of inducing specific regulatory T cells while preserving other T-cell functionality.
Yvon
Eric S
ES
Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin St, Houston, TX 77030, USA.
Vigouroux
Stephane
S
Rousseau
Raphael F
RF
Biagi
Ettore
E
Amrolia
Persis
P
Dotti
Gianpietro
G
Wagner
Hans-Joachim
HJ
Brenner
Malcolm K
MK
D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D001773:Blood Cells; D002135:Calcium-Binding Proteins; D002472:Cell Transformation, Viral; D003602:Cytotoxicity, Immunologic; D004854:Herpesvirus 4, Human; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007519:Isoantigens; D000072100:Jagged-1 Protein; D017493:Leukocyte Common Antigens; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007519:Isoantigens; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D017493:Leukocyte Common Antigens