Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation.
Activation of T cells is induced efficiently by dendritic cells (DC), but little is known about the role of DC in the regulation of T cell death. In this study, highly purified DC (DEC-205+, MHC class II(high), B7-1+ [CD80+], B7-2high [CD86high], CD40+, CD11c+) grown from normal mouse bone marrow in granulocyte-macrophage CSF + IL-4 were found to express FasL (CD95L) mRNA by reverse transcriptase PCR and to uniformly express FasL by both flow cytometric and immunocytochemical analyses. These cells, but not DC propagated from FasL-deficient (B6.gld) mice, induced dose-dependent increases in DNA fragmentation in Fas+ Jurkat T cells over 18 h coculture. Addition of mouse Fas-Fc fusion protein at the start of the cultures diminished this effect. Even at high relative concentrations, however, B7-2high DC induced only low levels of DNA fragmentation in Con A or alloactivated splenic T cells, as determined by radio- or spectrofluorometric assays and by in situ nick-end labeling. However, in the presence of CTLA4Ig, a molecule that blocks the B7-CD28 costimulatory pathway, DC that failed to stimulate in primary MLR induced markedly augmented levels of apoptosis in alloactivated T cells. CTLA4Ig treatment also increased the level of DNA fragmentation induced by FasL-deficient DC, indicating the existence of additional potential (Fas-independent) pathways of DC-induced T cell death. These findings suggest that the costimulatory (B7-CD28) and T cell death-inducing pathways may play important counter-regulatory roles in dictating the outcome of (allogeneic) DC-T cell interactions.
Lu
L
L
Thomas E. Starzl Transplantation Institute and the Department of Surgery, University of Pittsburgh, PA 15213, USA.
Qian
S
S
Hershberger
P A
PA
Rudert
W A
WA
Lynch
D H
DH
Thomson
A W
AW
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D018122:B7-1 Antigen / Q000032:analysis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D053938:DNA Fragmentation; D003713:Dendritic Cells / Q000502:physiology*; D053222:Fas Ligand Protein; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology; D013053:Spectrophotometry; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000502:physiology*
D000954:Antigens, Surface; D018122:B7-1 Antigen; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins