title: Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity.
abstract: Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8(+) memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Antonia M S
authors.initials: AM
authors.lastname: Müller
authors.forename: Sumana
authors.initials: S
authors.lastname: Shashidhar
authors.forename: Natascha J
authors.initials: NJ
authors.lastname: Küpper
authors.forename: Holbrook E K
authors.initials: HE
authors.lastname: Kohrt
authors.forename: Mareike
authors.initials: M
authors.lastname: Florek
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.forename: Janice M
authors.initials: JM
authors.lastname: Brown
authors.forename: Judith A
authors.initials: JA
authors.lastname: Shizuru
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006566:Herpesviridae Infections / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000276:immunology*; D007114:Immunization; D016131:Lymphocyte Subsets / Q000276:immunology; D008231:Lymphopenia / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus; D013601:T-Lymphocytes / Q000166:cytology / Q000637:transplantation*; D014775:Virus Activation / Q000276:immunology
chemical_list: D000939:Epitopes