title: Interactions between NKT cells and Tregs are required for tolerance to combined bone marrow and organ transplants.
abstract: We used a model of combined bone marrow and heart transplantation, in which tolerance and stable chimerism is induced after conditioning with fractionated irradiation of the lymphoid tissues and anti-T-cell antibodies. Graft acceptance and chimerism required host CD4(+)CD25(+) Treg production of IL-10 that was in-turn enhanced by host invariant natural killer (NK) T-cell production of IL-4. Up-regulation of PD-1 on host Tregs, CD4(+)CD25(-) conventional T (Tcon) cells, and CD8(+) T cells was also enhanced by NKT cell production of IL-4. Up-regulated PD-1 expression on Tregs was linked to IL-10 secretion, on CD8(+) T cells was linked to Tim-3 expression, and on CD4(+) Tcon cells was associated with reduced IFNγ secretion. Changes in the expression of PD-1 were induced by the conditioning regimen, and declined after bone marrow transplantation. In conclusion, NKT cells in this model promoted changes in expression of negative costimulatory receptors and anti-inflammatory cytokines by Tregs and other T-cell subsets in an IL-4-dependent manner that resulted in tolerance to the bone marrow and organ grafts.
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 296 Campus Drive, Stanford, CA 94305, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hongo
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Tang
authors.forename: Suparna
authors.initials: S
authors.lastname: Dutt
authors.forename: Roland G
authors.initials: RG
authors.lastname: Nador
authors.forename: Samuel
authors.initials: S
authors.lastname: Strober
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism; D000961:Antilymphocyte Serum / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D016027:Heart Transplantation / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D019172:Transplantation Conditioning / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000943:Antigens, Differentiation; D000961:Antilymphocyte Serum; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma