title: Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality.
abstract: Graft-versus-host disease (GVHD) is driven by extensive activation and proliferation of alloreactive donor T cells causing significant morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Invariant natural killer T (iNKT) cells are a potent immunoregulatory T-cell subset in both humans and mice. Here, we explored the role of adoptively transferred third-party CD4(+) iNKT cells for protection from lethal GVHD in a murine model of allogeneic HCT across major histocompatibility barriers. We found that low numbers of CD4(+) iNKT cells from third-party mice resulted in a significant survival benefit with retained graft-versus-tumor effects. In vivo expansion of alloreactive T cells was diminished while displaying a T helper cell 2-biased phenotype. Notably, CD4(+) iNKT cells from third-party mice were as protective as CD4(+) iNKT cells from donor mice although third-party CD4(+) iNKT cells were rejected early after allogeneic HCT. Adoptive transfer of third-party CD4(+) iNKT cells resulted in a robust expansion of donor CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) that were required for protection from lethal GVHD. However, in vivo depletion of myeloid-derived suppressor cells abrogated both Treg expansion and protection from lethal GVHD. Despite the fact that iNKT cells are a rare cell population, the almost unlimited third-party availability and feasibility of in vitro expansion provide the basis for clinical translation.
authors: Division of Blood and Marrow Transplantation, Department of Medicine.
authors: Dominik
authors: D
authors: Schneidawind
authors: Division of Blood and Marrow Transplantation, Department of Medicine.
authors: Jeanette
authors: J
authors: Baker
authors: Division of Blood and Marrow Transplantation, Department of Medicine.
authors: Antonio
authors: A
authors: Pierini
authors: Department of Pathology, and.
authors: Corina
authors: C
authors: Buechele
authors: Department of Comparative Medicine, Stanford University, Stanford, CA.
authors: Richard H
authors: RH
authors: Luong
authors: Division of Blood and Marrow Transplantation, Department of Medicine.
authors: Everett H
authors: EH
authors: Meyer
authors: Division of Blood and Marrow Transplantation, Department of Medicine.
authors: Robert S
authors: RS
authors: Negrin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology* / Q000637:transplantation*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019610:Cytoprotection / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality* / Q000517:prevention & control*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000502:physiology* / Q000637:transplantation*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology