Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution.
Despite recent progress in our understanding of the biology of T-cell homeostasis, clinically available therapies to substantially improve immune reconstitution in patients sustaining T-cell depletion are lacking. T cells are regenerated via a dynamic interplay between thymopoiesis and thymic-independent homeostatic peripheral expansion (HPE). Using athymic mice subjected to T-cell depletion, we observed that HPE is critically dependent on dendritic cells (DCs) for presentation of antigen, raising the possibility that the availability of DCs might be limiting in vivo for HPE to occur efficiently. Indeed, flt3 ligand (flt3L) treatment of athymic mice subjected to T-cell depletion (without DC depletion) substantially enhanced HPE and improved immune competence. Following bone marrow transplantation (BMT) in athymic hosts, both dendritic cells and T cells were profoundly depleted and flt3L therapy restored DC numbers and enhanced HPE. In addition, thymus-bearing BMT recipients treated with flt3L regenerated increased numbers of thymic-dependent progeny with increased numbers of T-cell receptor excision circle (TREC)-positive T cells, indicating increased thymopoiesis. Therefore, flt3L is a potent immunorestorative agent that enhances both thymic-dependent and thymic-independent pathways of T-cell regeneration.
Fry
Terry J
TJ
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. tf60y@nih.gov
Sinha
Manoj
M
Milliron
Matthew
M
Chu
Yu-Waye
YW
Kapoor
Veena
V
Gress
Ronald E
RE
Thomas
Elaine
E
Mackall
Crystal L
CL
D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006487:Hemostasis; D006801:Humans; D007107:Immune System / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D008565:Membrane Proteins / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000187:drug effects*; D013601:T-Lymphocytes / Q000502:physiology; D013950:Thymus Gland / Q000276:immunology / Q000502:physiology*
D008565:Membrane Proteins; C084881:flt3 ligand protein