Autocrine IFNγ controls the regulatory function of lymphoproliferative double negative T cells.
TCRαβ(+) CD4(-)CD8(-)NK(-) double negative T cells (DN T cells) can act as regulatory T cells to inhibit allograft rejection and autoimmunity. Their role in graft-versus-host disease and mechanisms of suppression remain elusive. In this study, we demonstrate that DN T cells can inhibit CD4(+) T cell-mediated GVHD in a semi-allogeneic model of bone marrow transplantation. Furthermore, we present evidence of a novel autocrine IFNγ signaling pathway in Fas-deficient C57BL/6.lpr (B6.lpr) DN T cells. B6.lpr DN T cells lacking IFNγ or its receptor were impaired in their ability to suppress syngeneic CD4(+) T cells responding to alloantigen stimulation both in vitro and in vivo. Autocrine IFNγ signaling was required for sustained B6.lpr DN T cell IFNγ secretion in vivo and for upregulation of surface Fas ligand expression during TCR stimulation. Fas ligand (FasL) expression by B6.lpr DN T cells permitted lysis of activated CD4(+) T cells and was required for suppression of GVHD. Collectively, our data indicate that DN T cells can inhibit GVHD and that IFNγ plays a critical autocrine role in controlling the regulatory function of B6.lpr DN T cells.
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Stephen C
SC
Juvet
Mei
M
Han
Ramesh
R
Vanama
Betty
B
Joe
Edward Y
EY
Kim
Fei Linda
FL
Zhao
Caroline
C
Jeon
Oyedele
O
Adeyi
Li
L
Zhang
D000818:Animals; D019898:Autocrine Communication / Q000276:immunology*; D016026:Bone Marrow Transplantation; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
D053222:Fas Ligand Protein; D007371:Interferon-gamma