title: Modification of T cell responses by stem cell mobilization requires direct signaling of the T cell by G-CSF and IL-10.
abstract: The majority of allogeneic stem cell transplants are currently undertaken using G-CSF mobilized peripheral blood stem cells. G-CSF has diverse biological effects on a broad range of cells and IL-10 is a key regulator of many of these effects. Using mixed radiation chimeras in which the hematopoietic or nonhematopoietic compartments were wild-type, IL-10(-/-), G-CSFR(-/-), or combinations thereof we demonstrated that the attenuation of alloreactive T cell responses after G-CSF mobilization required direct signaling of the T cell by both G-CSF and IL-10. IL-10 was generated principally by radio-resistant tissue, and was not required to be produced by T cells. G-CSF mobilization significantly modulated the transcription profile of CD4(+)CD25(+) regulatory T cells, promoted their expansion in the donor and recipient and their depletion significantly increased graft-versus-host disease (GVHD). In contrast, stem cell mobilization with the CXCR4 antagonist AMD3100 did not alter the donor T cell's ability to induce acute GVHD. These studies provide an explanation for the effects of G-CSF on T cell function and demonstrate that IL-10 is required to license regulatory function but T cell production of IL-10 is not itself required for the attenuation GVHD. Although administration of CXCR4 antagonists is an efficient means of stem cell mobilization, this fails to evoke the immunomodulatory effects seen during G-CSF mobilization. These data provide a compelling rationale for considering the immunological benefits of G-CSF in selecting mobilization protocols for allogeneic stem cell transplantation.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia;
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.forename: Laetitia
authors.initials: L
authors.lastname: Le Texier
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Helen
authors.initials: H
authors.lastname: Morris
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lineburg
authors.forename: Lucie
authors.initials: L
authors.lastname: Leveque
authors.forename: Alistair L
authors.initials: AL
authors.lastname: Don
authors.forename: Kate A
authors.initials: KA
authors.lastname: Markey
authors.forename: Slavica
authors.initials: S
authors.lastname: Vuckovic
authors.forename: Frederik O
authors.initials: FO
authors.lastname: Bagger
authors.forename: Glen M
authors.initials: GM
authors.lastname: Boyle
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
mesh_terms: D000818:Animals; D001596:Benzylamines; D049109:Cell Proliferation / Q000187:drug effects; D000080027:Cyclams; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology* / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006571:Heterocyclic Compounds / Q000276:immunology / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D033581:Stem Cell Transplantation / Q000379:methods; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000276:immunology
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor