Blood Stem Cell Activity Is Arrested by Th1-Mediated Injury Preventing Engraftment following Nonmyeloablative Conditioning.
T cells are widely used to promote engraftment of hematopoietic stem cells (HSCs) during an allogeneic hematopoietic cell transplantation. Their role in overcoming barriers to HSC engraftment is thought to be particularly critical when patients receive reduced doses of preparative chemotherapy and/or radiation compared with standard transplantations. In this study, we sought to delineate the effects CD4+cells on engraftment and blood formation in a model that simulates clinical hematopoietic cell transplantation by transplanting MHC-matched, minor histocompatibility-mismatched grafts composed of purified HSCs, HSCs plus bulk T cells, or HSCs plus T cell subsets into mice conditioned with low-dose irradiation. Grafts containing conventional CD4+T cells caused marrow inflammation and inhibited HSC engraftment and blood formation. Posttransplantation, the marrows of HSCs plus CD4+cell recipients contained IL-12-secreting CD11c+cells and IFN-γ-expressing donor Th1 cells. In this setting, host HSCs arrested at the short-term stem cell stage and remained in the marrow in a quiescent cell cycling state (G0). As a consequence, donor HSCs failed to engraft and hematopoiesis was suppressed. Our data show that Th1 cells included in a hematopoietic allograft can negatively impact HSC activity, blood reconstitution, and engraftment of donor HSCs. This potential negative effect of donor T cells is not considered in clinical transplantation in which bulk T cells are transplanted. Our findings shed new light on the effects of CD4+T cells on HSC biology and are applicable to other pathogenic states in which immune activation in the bone marrow occurs such as aplastic anemia and certain infectious conditions.
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305; anmuelle@stanford.edu jshizuru@stanford.edu.|Department of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland.
Antonia M S
AM
Müller
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Mareike
0000-0001-6049-3482
M
Florek
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Holbrook E K
HE
Kohrt
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Natascha J
NJ
Küpper
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305; and.
Alexander
0000-0002-5165-4173
A
Filatenkov
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Jessica A
JA
Linderman
Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
Husein
0000-0002-2491-1365
H
Hadeiba
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Robert S
RS
Negrin
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305; anmuelle@stanford.edu jshizuru@stanford.edu.
Judith A
JA
Shizuru
D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002453:Cell Cycle; D006085:Graft Survival; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000502:physiology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000072916:Peripheral Blood Stem Cells / Q000276:immunology / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology*; D014019:Tissue Donors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning
D018664:Interleukin-12; D007371:Interferon-gamma