Cytokine expanded myeloid precursors function as regulatory antigen-presenting cells and promote tolerance through IL-10-producing regulatory T cells.
The initiation of graft-vs-host disease (GVHD) after stem cell transplantation is dependent on direct Ag presentation by host APCs, whereas the effect of donor APC populations is unclear. We studied the role of indirect Ag presentation in allogenic T cell responses by adding populations of cytokine-expanded donor APC to hemopoietic grafts that would otherwise induce lethal GVHD. Progenipoietin-1 (a synthetic G-CSF/Flt-3 ligand molecule) and G-CSF expanded myeloid dendritic cells (DC), plasmacytoid DC, and a novel granulocyte-monocyte precursor population (GM) that differentiate into class II+,CD80/CD86+,CD40- APC during GVHD. Whereas addition of plasmacytoid and myeloid donor DC augmented GVHD, GM cells promoted transplant tolerance by MHC class II-restricted generation of IL-10-secreting, Ag-specific regulatory T cells. Importantly, although GM cells abrogated GVHD, graft-vs-leukemia effects were preserved. Thus, a population of cytokine-expanded GM precursors function as regulatory APCs, suggesting that G-CSF derivatives may have application in disorders characterized by a loss of self-tolerance.
MacDonald
Kelli P A
KP
Queensland Institute of Medical Research, Herston, Australia.
Rowe
Vanessa
V
Clouston
Andrew D
AD
Welply
Joseph K
JK
Kuns
Rachel D
RD
Ferrara
James L M
JL
Thomas
Ranjeny
R
Hill
Geoffrey R
GR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002499:Centrifugation, Density Gradient; D018920:Coculture Techniques; D003115:Colony-Stimulating Factors / Q000008:administration & dosage*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006098:Granulocytes / Q000166:cytology / Q000637:transplantation; D006183:H-2 Antigens / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000637:transplantation; D023461:Myeloid Progenitor Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D023001:Transplantation Tolerance
D003115:Colony-Stimulating Factors; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D011994:Recombinant Proteins; C434603:progenipoietin-1; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor