Expansion of peripheral naturally occurring T regulatory cells by Fms-like tyrosine kinase 3 ligand treatment.
Fms-like tyrosine kinase 3 ligand (FLT3L) plays a major role in dendritic cell (DC) biology. Deficiency of FLT3L causes a dramatic decrease in DC numbers, whereas increasing its availability (by repetitive injections for 7-10 days) leads to a 10-fold increase in DC numbers. In this study, we show that FLT3L treatment indirectly leads to an expansion of peripheral naturally occurring T regulatory cells (NTregs). The FLT3L-induced increase in NTregs was still observed in thymectomized mice, ruling out the role of the thymus in this mechanism. Instead, the increased number of NTregs was due to proliferation of preexisting NTregs, most likely due to favored interactions with increased number of DCs. In vitro, we show that DCs induce regulatory T-cell (Treg) proliferation by direct cell contact and in an interleukin-2-dependent, T-cell receptor-independent manner. FLT3L could prevent death induced by acute graft-versus-host disease (GVHD). This study demonstrates unique aspects in the regulation of Treg homeostasis by DCs, which were unappreciated until now. It also reinforces the relevance of FLT3L treatment in GVHD by its ability to increase both the number of tolerizing DCs and NTregs.
Swee
Lee Kim
LK
Departement Biomedizin Basel, University of Basel, Switzerland.
Bosco
Nabil
N
Malissen
Bernard
B
Ceredig
Rhodri
R
Rolink
Antonius
A
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication; D002454:Cell Differentiation; D002455:Cell Division; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D006086:Graft vs Host Disease / Q000517:prevention & control / Q000628:therapy*; D007376:Interleukin-2 / Q000502:physiology; D018655:Lymphocyte Count; D008565:Membrane Proteins / Q000172:deficiency / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects*; D013934:Thymectomy
D007376:Interleukin-2; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; C084881:flt3 ligand protein