title: Stromal-Derived Factor-1α and Interleukin-7 Treatment Improves Homeostatic Proliferation of Naïve CD4(+) T Cells after Allogeneic Stem Cell Transplantation.
abstract: Graft-versus-host disease (GVHD) impairs immune reconstitution after allogeneic stem cell transplantation (allo-SCT) and effective therapies aimed at restoring T cell counts in GVHD patients have yet to be developed. During GVHD, CD4(+) T cell reconstitution is particularly affected and current models hold that GVHD insult to the peripheral lymphoid niche is responsible for this effect. Here, we show that naïve CD4(+) T cell homeostatic proliferation (HP) is lost during GVHD because of low systemic IL-7 and impaired dendritic cell (DC) regeneration. We assessed factors involved in DC differentiation and found that although fms-like tyrosine kinase 3 ligand (Flt3-L) levels were normal, stromal-derived factor-1α (SDF-1α) was diminished in the blood of GVHD mice. Unlike Flt3-L treatment, the administration of SDF-1α specifically increased CD8α(+) DC numbers and did not worsen GVHD. Importantly, CD4(+) T cell HP was enhanced only when IL-7 and SDF-1α or Flt3L were coadministered, confirming the crucial role of DCs and IL-7 in restoring CD4(+) T cell regeneration during GVHD. Altogether, our results indicate that CD8α(+) DCs are part of the peripheral niche that controls CD4(+) T cell HP and that their depletion, combined with low systemic IL-7, explains how GVHD constrains naïve CD4(+) T cell reconstitution after allo-SCT.
authors.affiliation: Department of Hematology-Oncology, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, Canada; Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Simon-David
authors.initials: SD
authors.lastname: Gauthier
authors.affiliation: Department of Hematology-Oncology, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Leboeuf
authors.affiliation: Department of Hematology-Oncology, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, Canada.
authors.forename: Renaud
authors.initials: R
authors.lastname: Manuguerra-Gagné
authors.affiliation: Department of Pathology, Institute for Research in Immunology and Cancer, Montréal, Québec, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Gaboury
authors.affiliation: Department of Hematology-Oncology, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, Canada; Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada. Electronic address: martin.guimond@umontreal.ca.
authors.forename: Martin
authors.initials: M
authors.lastname: Guimond
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D054377:Chemokine CXCL12 / Q000097:blood / Q000172:deficiency / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D015851:Interleukin-7 / Q000172:deficiency / Q000502:physiology / Q000627:therapeutic use*; D008212:Lymphocyte Depletion; D008565:Membrane Proteins / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020395:Receptors, Interleukin-7 / Q000172:deficiency; D011994:Recombinant Proteins / Q000627:therapeutic use; D017154:Stromal Cells / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C508605:IL7 protein, human; D015851:Interleukin-7; D008565:Membrane Proteins; D020395:Receptors, Interleukin-7; D011994:Recombinant Proteins; C084881:flt3 ligand protein; C415350:interleukin-7 receptor, alpha chain; C576410:interleukin-7, mouse
keywords: CD4(+) T lymphocytes; Dendritic cells; Flt3-ligand; Graft-versus-host disease; Homeostatic proliferation; Interleukin-7; Stromal-derived factor-1α