Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment.
Redirection of immune responses by manipulation of antigen-presenting cells is an emerging strategy for immunosuppressive treatment of autoimmune diseases. In vivo expansion of dendritic cells (DC) by Fms-like tyrosine kinase-3 (Flt3)-Ligand (FL) treatment was shown to delay diabetes onset in the NOD model of autoimmune diabetes. However, we show here that Flt3 stimulation actually accelerates autoimmunity when autoreactive CD8 T cells are detectable in blood prior to treatment. With autoreactive CD8 cells present, the capacity of FL to expand DCs and induce Treg remained intact, but both numbers and the functional response of islet-specific CD8s were boosted. Also, the inhibitory receptor PD-1 on (autoreactive) CD8 T cells and its ligand PD-L1 on Treg were no longer upregulated. These data highlight the need to pre-screen for T cell autoreactivity prior to generalized DC expansion and illustrate how accelerated disease can occur when the intended initiation of regulatory mechanisms is impaired later in diabetogenesis.
Van Belle
Tom L
TL
Diabetes Center at San Diego, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
Juntti
Therese
T
Liao
Jeanette
J
von Herrath
Matthias G
MG
D000818:Animals; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology; D008565:Membrane Proteins / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D016896:Treatment Outcome
D008565:Membrane Proteins; C084881:flt3 ligand protein