A Crucial Role for Host APCs in the Induction of Donor CD4+CD25+ Regulatory T Cell-Mediated Suppression of Experimental Graft-versus-Host Disease

Tawara, Isao; Shlomchik, Warren D.; Jones, Angela; Zou, Weiping; Nieves, Evelyn; Liu, Chen; Toubai, Tomomi; Duran‐Struuck, Raimon; Sun, Yaping; Clouthier, Shawn G.; Evers, Rebecca; Lowler, Kathleen P.; Levy, Robert B.; Reddy, Pavan

doi:10.4049/jimmunol.1001625

Cited by 45 publications

(40 citation statements)

References 51 publications

(52 reference statements)

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“…Because host hematopoietic-derived APCs can also negatively regulate GVH responses, 37,38 our data indicate that strategies that promote the regulatory APC subsets [39][40][41][42] might be more effective than elimination of hematopoietic-derived activating APC subsets. 28,[43][44][45] Importantly, our data indicate that regulating the process of Ag presentation, rather than targeting any specific host hematopoietic-derived cellular subsets that are capable of activating alloreactive donor T cells, might be a more desirable strategy for mitigating GVHD. …”

Section: Discussionmentioning

confidence: 99%

Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic–derived antigen-presenting cells

Toubai

Tawara

Sun

et al. 2012

Blood

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IntroductionAg presentation on radiosensitive host hematopoiesis-derived APCs to the alloreactive donor T cells is considered to be obligatory for the induction of acute GVHD. 1-9 However, under certain conditions, whether clinically relevant minor Ags can induce GVHD in the absence of functional radiosensitive host hematopoietic APCs is not known. [6][7][8]10 Clinical data from MHC-matched BMT show that male recipients from female donors (F3M) are at a greater risk of developing GVHD 9 and show H-Y-specific alloresponses. [11][12][13][14] These clinical data suggest a strong correlation between H-Y Ag disparity and GVHD. However, in the context of HLA-matched clinical F3M BMT, the donors are also likely to be mismatched with the recipients at multiple minor Ags. Therefore, whether H-Y disparity alone is sufficient for causing clinical acute GVHD is not known. The experimental evidence for the causative role of H-Y Ags in GVHD and mortality has not been reported. Furthermore, the relevance of donor T-cell alloreactivity against a single minor Ag and mechanisms of its presentation in causing GVHD are not known. [1][2][3][4][5] Although some studies have suggested that high doses of TCR transgenic (Tg) T cells can cause GVHD, its severity was limited and was in the context of MHC mismatch or against minor Ags with unknown clinical relevance. 15,16 With the use of both H-Y-specific Tg and non-Tg T cells in multiple well-established BM chimeras we demonstrate, in contrast to the existing notion, that presentation of clinically relevant minor H-Y Ag by host radiosensitive hematopoieticderived APCs is not obligatory for induction of acute GVHD. 3,[6][7][8]10,17 Our data further suggest that in the absence of radiosensitive host hematopoietic-derived APCs, when sufficient numbers of alloreactive donor T cells are infused, nonhematopoietic-derived cells such as endothelial and certain epithelial cells activate alloreactive T cells, might induce GVHD. Methods MiceMale and female C57BL/6 (B6, H-2 b , CD45.2 ϩ ), B6 Ly5.2 (H-2 b , CD45.1 ϩ ), and BALB/c (H-2 d ) mice were purchased from The Jackson 17 and MataHari (RAG-1 Ϫ background, CD8 ϩ Tg, H-2 b , CD45.2 ϩ , H-2D b -restricted) mice 18 were obtained from Taconic. All animals were cared for under regulations reviewed and approved by the University Committee on Use and Care of Animals of the University of Michigan, based on University Laboratory Animal Medicine guidelines. Generation of BM chimerasWe administered 1100 cGy total body irradiation ( 137 Cs source) to mice and then injected them intravenously with 5 ϫ 10 6 BM cells with 5 ϫ 10 6 whole spleen cells from donor mice on day Ϫ1. For generating MHC class I-deficient (␤2m-KO) BM chimeras, recipient mice were treated with 200 g of anti-NK1.1 mAb (PK136) on days Ϫ2 and Ϫ1. 6 The peripheral blood from sentinel mice were analyzed for donor chimerism at 3 months and found to show Ͼ 98% donor chimerism in all cell lineages. The CD11c ϩ cells in the splenocytes from these animals also showed Ͼ 95% donor chimerism. BMTBMT...

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Section: Discussionmentioning

confidence: 99%

Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic–derived antigen-presenting cells

Toubai

Tawara

Sun

et al. 2012

Blood

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“…16,17 However, graft-versus-host disease remains a major barrier for the clinical application of HLAmismatched bone marrow transplantation. [18][19][20] The protective effect of donor CD4 1 CD25 1 Tregs in graft-versus-host disease has been previously demonstrated. 21,22 In addition to the inhibition of T effector cells (Teffs) by CD4 1 CD25 1 Tregs, whether allogeneic donor CD4 1 CD25 1 Tregs has regulatory effects on recipient macrophages or other antigen-presenting cells in vivo has not yet been determined.…”

Section: Introductionmentioning

confidence: 92%

“…CD4 1 T responders (2310 5 ) and macrophage stimulators (1310 5 ), which were pre-treated with 50 mg/mL mitomycin C, were incubated in triplicate in 0.2 mL medium in Ubottomed 96-well microplates (Costar) at 37 uC in 5% CO 2 . 18,28,34,35 The plates were pulsed with 1 mCi of 3 H-labeled thymidine (radioactivity, 185 GBq/mM; Atomic Energy Research Establishment, Beijing, China) per well on day 3, and after 18 h of further incubation, the cells were harvested onto glass fiber filters with an automatic cell harvester (Tomtec, Toku, Finland). The samples were assayed in a .…”

Section: Detection Of Ifn-c Il-4 and Il-10mentioning

confidence: 99%

Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4+CD25+ regulatory T cells

Liu

Hou

et al. 2012

Cell Mol Immunol

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CD4 1 CD25 1 regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4 1 CD25 1 Tregs can regulate recipient mouse macrophages is unknown. The effect of allogeneic donor CD4 1 CD25 1 Tregs on recipient mouse resident F4/80 1 macrophages was investigated using a mouse model in which allogeneic donor CD4 1 CD25 1 Tregs were adoptively transferred into the peritoneal cavity of host NOD-scid mice. The phenotype and function of the recipient macrophages were then assayed. The peritoneal F4/80 1 macrophages in the recipient mice that received the allogeneic CD4 1 CD25 1 Tregs expressed significantly higher levels of CD23 and programmed cell death-ligand 1(PD-L1) and lower levels of CD80, CD86, CD40 and MHC II molecules compared to the mice that received either allogeneic CD4 1 CD25 2 T cells (Teffs) or no cells. The resident F4/80 1 macrophages of the recipient mice injected with the allogeneic donor CD4 1 CD25 1 Tregs displayed significantly increased phagocytosis of chicken red blood cells (cRBCs) and arginase activity together with increased IL-10 production, whereas these macrophages also showed decreased immunogenicity and nitric oxide (NO) production. Blocking arginase partially but significantly reversed the effects of CD4 1 CD25 1 Tregs with regard to the induction of the M2 macrophages in vivo. Therefore, the allogeneic donor CD4 1 CD25 1 Tregs can induce the M2 macrophages in recipient mice at least in part via an arginase pathway. We have provided in vivo evidence to support the unknown pathways by which allogeneic donor CD4 1 CD25 1 Tregs regulate innate immunity in recipient mice by promoting the differentiation of M2 macrophages.

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“…These features have been interpreted to indicate that tTregs may be preoccupied with ensuring tolerance to self-antigens, while pTregs operate to moderate responses to certain "foreign" antigens that might be found in the gut microbiome or in the fetus during pregnancy (33). Given the potential cross-reactivity of the T cell receptor repertoire, a proportion of tTregs would be expected to exhibit alloreactivity exploitable for tolerance induction (34,35). The conventional repertoire of pTregs also points to a real prospect for selective tolerizing vaccinations to foreign graft antigens (36).…”

Section: Tregs and Their Roles In Transplantation Tolerancementioning

confidence: 99%

Harnessing FOXP3+ regulatory T cells for transplantation tolerance

Waldmann¹,

Hilbrands²,

Howie³

et al. 2014

J. Clin. Invest.

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Early demonstrations that mice could be tolerized to transplanted tissues with short courses of immunosuppressive therapy and that with regard to tolerance to self, CD4 + FOXP3 + regulatory T cells (Tregs) appeared to play a critical role, have catalyzed strategies to harness FOXP3-dependent processes to control rejection in human transplantation. This review seeks to examine the scientific underpinning for this new approach to finesse immunosuppression.

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A Crucial Role for Host APCs in the Induction of Donor CD4+CD25+ Regulatory T Cell-Mediated Suppression of Experimental Graft-versus-Host Disease

Cited by 45 publications

References 51 publications

Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic–derived antigen-presenting cells

Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic–derived antigen-presenting cells

Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4+CD25+ regulatory T cells

Harnessing FOXP3+ regulatory T cells for transplantation tolerance

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