Requirement for natural killer T (NKT) cells in the induction of allograft tolerance

Seino, Ken‐ichiro; Fukao, Katashi; Muramoto, Koji; Yanagisawa, Kazuhiko; Takada, Yasutsugu; Kakuta, Shigeru; Iwakura, Yoichiro; Kaer, Luc Van; Takeda, Kazuyoshi; Nakayama, Toshinori; Taniguchi, Masaru; Bashuda, Hisashi; Yagita, Hideo; Okumura, Ko

doi:10.1073/pnas.041608298

Cited by 234 publications

(194 citation statements)

References 66 publications

(69 reference statements)

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“…Many studies have suggested that an important physiological function of NKT cells is to control immune responses against infection and some tumors. In transplantation immunity, CD1d-dependent NKT cells are also thought to play a role in the induction of self 19 or allograft [20][21][22] or xenograft tolerance. 23 In a murine GVHD model, bone marrow DN NK1.1 þ T cells were observed to be important for preventing GVHD.…”

Section: Discussionmentioning

confidence: 99%

Recovery of Vα24+ NKT cells after hematopoietic stem cell transplantation

Haraguchi

Takahashi

Hiruma

et al. 2004

Bone Marrow Transplant

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Summary:Human Va24 þ natural killer T (NKT) cells have an invariant T-cell receptor-a chain and are activated in a CD1d-restricted manner. Va24 þ NKT cells are thought to regulate immune responses and to play important roles in the induction of allograft tolerance. In this report, we analyzed the recovery of Va24 þ NKT cells after hematopoietic stem cell transplantation and its correlation with graft-versus-host disease (GVHD). Patients who received a dose-reduced conditioning regimen, antithymocyte globulin-or CAMPATH-1H-containing conditioning regimen were excluded. NKT cells were reconstituted within 1 month after transplantation in peripheral blood stem cell transplantation recipients, while their numbers remained low for more than 1 year in bone marrow transplantation (BMT) recipients. The number of Va24 þ NKT cells in BMT recipients with acute GVHD was lower than that in patients without acute GVHD, and both the CD4 þ and CD4 À Va24 þ NKT subsets were significantly reduced. With regard to chronic GVHD, BMT recipients with extensive GVHD had significantly fewer Va24 þ NKT cells than other patients. Furthermore, the number of CD4 þ Va24 þ NKT cells was also significantly reduced in patients with chronic extensive GVHD. Our results raise the possibility that the number of Va24 þ NKT cells could be related to the development of GVHD.

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Section: Discussionmentioning

confidence: 99%

Recovery of Vα24+ NKT cells after hematopoietic stem cell transplantation

Haraguchi

Takahashi

Hiruma

et al. 2004

Bone Marrow Transplant

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“…Early interest in murine invariant CD1d-reactive T cells was sparked by their ability to rapidly produce large amounts of IL-4 and IFN-␥ after stimulation, 9,10,32 suggesting a role in the development of Th2- 64,65 Finally, invariant CD1d-reactive T cells promote tolerance in murine models of transplantation, such as cardiac allografts, 66 although the specific role of these cells in promoting tolerance of liver allografts is unknown. Therefore, under appropriate conditions, CD1d-reactive T cells can have anti-inflammatory and/or immunomodulatory properties.…”

Section: Role In Control Of Immune Responsesmentioning

confidence: 99%

To be or not to be NKT: Natural killer T cells in the liver

2004

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N KT cells are a diverse group of cells that share features of both classical T cells and natural killer (NK) cells, and have similarly diverse functions. One of the complexities in understanding NKT cells involves sorting through the various terminology that has been applied to them in the emerging literature. 1,2 Functionally, a major subset of these cells are defined by reactivity against CD1d, which is one of five known glycolipid-binding nonpolymorphic major histocompatibility complex class 1-like glycoproteins: CD1a through e. 3 These glycoproteins appear to have evolved to facilitate recognition of nonprotein antigens-specifically glycolipid antigens, including those present in the cell walls of mycobacterial species. CD1d is constitutively expressed on a number of hematopoietic-derived antigenpresenting cell (APC) types-including B cells and myeloid cells-and can be expressed by human T cells as well as healthy hepatocytes. Physiological ligands for CD1d remain poorly defined, although both glycolipids and hydrophobic peptides bind to CD1 family molecules. 4,5 Most antigen studies have used the synthetic glycolipid ␣-galactosylceramide (␣GalCer), which binds to CD1d and activates a specific subset of both murine and human NKT cells in vitro and in vivo. 5,6 CD1d is remarkably conserved across mammalian species, with mouse and human CD1d having greater than 90% sequence homology. 7 Consequently, murine CD1d-reactive T cells recognize human CD1d, and vice versa. 8 After activation, NKT cells are highly versatile and can produce large amounts of interferon gamma (IFN-␥) and interleukin (IL)-4 9,10 as prototypic type 1 and type 2 cytokines, respectively, as well as display NK/lymphokine-activated killing-like FasL-mediated or perforin-dependent CD1d-specific cytotoxicity 11-14 thus potentially contributing to protective and pathogenic responses against multiple infectious agents and tumors.CD1d is expressed by dendritic cells (DCs), and ␣Gal-Cer-loaded DCs mediate activation of invariant NKT cells. [15][16][17][18] Although peripheral NKT cells can recognize and respond to other CD1d ϩ cells, their in vivo activation may be initiated by interactions with DCs and possibly B cells. The interactions between invariant NKT cells and DCs share many features of interactions between conventional CD4 ϩ T cells and DCs. DCs pulsed with ␣GalCer stimulate NKT cells through T cell receptor (TCR) ligation. 2,19,20 NKT cell activation and IFN-␥ production are markedly enhanced by DC-produced IL-12, with an increase in the IL-12 receptor on activated NKT cells. 15,21,22 Conversely, invariant NKT cells also interact with ␣Gal-Cer-loaded DCs to enhance CD4 ϩ and CD8 ϩ T-cell responses 16,17,23,24 and with B cells to provide help for antibody production. 25 However, ␣Galcer is not a physiological antigen, and it is not yet clear whether physiological NKT-DC interactions are mediated by specific CD1d-presented antigens or are antigen independent.The classical CD1d-reactive NKT cell population expresses a highly restricted TCR r...

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“…2B). Since previous studies (15,23) indicated that the regulatory functions of NK1.1 ϩ T cells are mediated at least in part by IL-4 or IFN-␥, the survival of heart allografts was compared in IL-4 Ϫ/Ϫ , IFN-␥ Ϫ/Ϫ , and wild-type BALB/c hosts given the complete conditioning regimen. Fig.…”

Section: Role Of Cd1-reactive T Cells and Cytokines In Heart Graft Acmentioning

confidence: 99%

Immune Tolerance to Combined Organ and Bone Marrow Transplants After Fractionated Lymphoid Irradiation Involves Regulatory NK T Cells and Clonal Deletion

Higuchi

Zeng

Shizuru

et al. 2002

The Journal of Immunology

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104

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Immune tolerance to organ transplants has been reported in laboratory animals and in humans after nonmyeloablative conditioning of the host and infusion of donor bone marrow cells. We examined the mechanisms of immune tolerance to mouse cardiac allografts in MHC-mismatched hosts that developed mixed chimerism after posttransplant conditioning with a 2-wk course of multiple doses of lymphoid tissue irradiation, depletive anti-T cell Abs, and an infusion of donor bone marrow cells. When CD1−/− or Jα281−/− hosts with markedly reduced NK T cells were used instead of wild-type hosts, then the conditioning regimen failed to induce tolerance to the heart allografts despite the development of mixed chimerism. Tolerance could be restored to the CD1−/− hosts by infusing enriched T cells from the bone marrow of wild-type mice containing CD1-reactive T cells but not from CD1−/− host-type mice. Tolerance could not be induced in either IL-4−/− or IL-10−/− hosts given the regimen despite the development of chimerism and clonal deletion of host T cells to donor MHC-Ags in the IL-10−/− hosts. We conclude that immune tolerance to bone marrow transplants involves clonal deletion, and tolerance to heart allografts in this model also involves regulatory CD1-reactive NK T cells.

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Requirement for natural killer T (NKT) cells in the induction of allograft tolerance

Cited by 234 publications

References 66 publications

Recovery of Vα24+ NKT cells after hematopoietic stem cell transplantation

Recovery of Vα24+ NKT cells after hematopoietic stem cell transplantation

To be or not to be NKT: Natural killer T cells in the liver

Immune Tolerance to Combined Organ and Bone Marrow Transplants After Fractionated Lymphoid Irradiation Involves Regulatory NK T Cells and Clonal Deletion

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