Regulatory T cells and human myeloid dendritic cells promote tolerance via programmed death ligand-1.
Immunotherapy using regulatory T cells (Treg) has been proposed, yet cellular and molecular mechanisms of human Tregs remain incompletely characterized. Here, we demonstrate that human Tregs promote the generation of myeloid dendritic cells (DC) with reduced capacity to stimulate effector T cell responses. In a model of xenogeneic graft-versus-host disease (GVHD), allogeneic human DC conditioned with Tregs suppressed human T cell activation and completely abrogated posttransplant lethality. Tregs induced programmed death ligand-1 (PD-L1) expression on Treg-conditioned DC; subsequently, Treg-conditioned DC induced PD-L1 expression in vivo on effector T cells. PD-L1 blockade reversed Treg-conditioned DC function in vitro and in vivo, thereby demonstrating that human Tregs can promote immune suppression via DC modulation through PD-L1 up-regulation. This identification of a human Treg downstream cellular effector (DC) and molecular mechanism (PD-L1) will facilitate the rational design of clinical trials to modulate alloreactivity.
Amarnath
Shoba
S
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. samarnath@mail.nih.gov
Costanzo
Carliann M
CM
Mariotti
Jacopo
J
Ullman
Jessica L
JL
Telford
William G
WG
Kapoor
Veena
V
Riley
James L
JL
Levine
Bruce L
BL
June
Carl H
CH
Fong
Timothy
T
Warner
Noel L
NL
Fowler
Daniel H
DH
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D060890:B7-H1 Antigen; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human