title: CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells.
abstract: Dysregulated donor T cells lead to destruction of host tissues resulting in graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We investigated the impact of highly purified (>95%) donor CD4(+) invariant natural killer T (iNKT) cells on GVHD in a murine model of allogeneic HCT. We found that low doses of adoptively transferred donor CD4(+) iNKT cells protect from GVHD morbidity and mortality through an expansion of donor CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). These Tregs express high levels of the Ikaros transcription factor Helios and expand from the Treg pool of the donor graft. Furthermore, CD4(+) iNKT cells preserve T-cell-mediated graft-versus-tumor effects. Our studies reveal new aspects of the cellular interplay between iNKT cells and Tregs in the context of tolerance induction after allogeneic HCT and set the stage for clinical translation.
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schneidawind
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pierini
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine.
authors.forename: Maite
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine.
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.affiliation: Department of Pathology, and.
authors.forename: Corina
authors.initials: C
authors.lastname: Buechele
authors.affiliation: Department of Comparative Medicine, Stanford University, Stanford, CA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Luong
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine.
authors.forename: Everett H
authors.initials: EH
authors.lastname: Meyer
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit