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. 2018 May 25;16(1):144.
doi: 10.1186/s12967-018-1519-2.

Regulatory γδ T cells induced by G-CSF participate in acute graft-versus-host disease regulation in G-CSF-mobilized allogeneic peripheral blood stem cell transplantation

Li Xuan  1 , Xiuli Wu  2 , Dan Qiu  2 , Li Gao  1 , Hui Liu  1 , Zhiping Fan  1 , Fen Huang  1 , Zhenyi Jin  2 , Jing Sun  1 , Yangqiu Li  3 , Qifa Liu  4
Affiliations

Regulatory γδ T cells induced by G-CSF participate in acute graft-versus-host disease regulation in G-CSF-mobilized allogeneic peripheral blood stem cell transplantation

Li Xuan et al. J Transl Med. .

Abstract

Background: The immunomodulatory effects of granulocyte colony-stimulating factor (G-CSF) on T cells result in a low incidence of acute graft-versus-host disease (aGVHD) in G-CSF-mobilized allogeneic peripheral blood stem cell transplantation (G-PBSCT). However, the exact mechanism remains unclear. Regulatory γδ T cells (γδTregs), characterized by the presence of TCRγδ and Foxp3, have aroused great concern in the maintenance of immune tolerance. We hypothesized that γδTregs might involve in the immunomodulatory effects of G-CSF mobilization. VSports手机版.

Methods: The expression and immunomodulatory function of γδTreg subsets in peripheral blood of donors before and after G-CSF treatment in vivo and in vitro were evaluated by flow cytometry and CFSE assays. To investigate the effects of γδTregs on aGVHD, the association between γδTreg subsets in grafts and aGVHD in recipients was estimated. V体育安卓版.

Results: The proportions of Vδ1Tregs, CD27+Vδ1Tregs and CD25+Vδ1Tregs were significantly increased in peripheral blood after G-CSF treatment in vivo. γδTregs could be generated in vitro by stimulating with anti-TCRγδ in the presence of G-CSF. The immune phenotype, proliferation suppression function, and cytokine secretion of G-CSF-induced γδTregs were similar to that of transforming growth factor-β (TGF-β)-induced γδTregs. The clinical data demonstrated that the proportion of CD27+Vδ1Tregs in grafts was significantly lower in the patients who experienced aGVHD than in those who did not develop aGVHD (P = 0. 028), and the proportions of other γδTreg subsets in grafts did not differ significantly between the two groups. The best cutoff value for CD27+Vδ1Treg proportion in grafts in prediction of aGVHD was 0. 33%, with an area under the curve value of 0. 725 (P = 0. 043). Eight patients (26. 7%) were classified as the low-CD27+Vδ1Treg group (< 0. 33%), and 22 patients (73. 3%) as the high-CD27+Vδ1Treg group (≥ 0. 33%). The incidence of aGVHD was higher in the low-CD27+Vδ1Treg group than in the high-CD27+Vδ1Treg group (75 V体育ios版. 0% versus 22. 7%, P = 0. 028). .

Conclusions: G-CSF could induce the generation of γδTregs in vivo and in vitro, and γδTregs might participate in aGVHD regulation in G-PBSCT. VSports最新版本.

Keywords: Acute graft-versus-host disease; Allogeneic peripheral blood stem cell transplantation; Granulocyte colony-stimulating factor; Regulatory γδ T cells V体育平台登录. .

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Figures

Fig. 1
Fig. 1
γδ T cell subsets in PBMCs of donors before and after G-CSF treatment in vivo. a, b CD27 and CD25 expression in γδTregs, Vδ1Tregs and Vδ2Tregs in PBMCs from 30 donors before (a) and after (b) G-CSF treatment in vivo (the figures are representative of one case). c Percentages of total γδ T cells, Vδ1 T cells, Vδ2 T cells, γδTregs, Vδ1Tregs and Vδ2Tregs in PBMCs of 30 donors before and after G-CSF treatment in vivo. d Percentages of CD27+γδTregs, CD27+Vδ1Tregs, CD27+Vδ2Tregs, CD25+γδTregs, CD25+Vδ1Tregs and CD25+Vδ2Tregs in PBMCs of 30 donors before and after G-CSF treatment in vivo. *P < 0.05
Fig. 2
Fig. 2
Proliferation of γδTreg subsets following anti-TCRγδ combined with G-CSF and/or TGF-β induction. a Kinetics of γδTreg proliferation following G-CSF or TGF-β induction during a 12-day culture period. b Proportions of γδTregs, Vδ1Tregs and Vδ2Tregs in freshly isolated PBMCs. c–e The expression of CD27 and CD25 phenotype on γδTregs (c), Vδ1Tregs (d) and Vδ2Tregs (e) in γδ T cells in the three induction and control groups on day 9 of culture. The data are representative of results from independent experiments of 5 healthy donors. f Proportions of γδTregs, Vδ1Tregs and Vδ2Tregs in γδ T cells in the three inductions and control groups on day 9 of culture. g Proportions of CD25+γδTregs, CD25+Vδ1Tregs, CD25+Vδ2Tregs, CD27+γδTregs, CD27+Vδ1Tregs and CD27+Vδ2Tregs in γδ T cells in the three inductions and control groups on day 9 of culture. *P < 0.05
Fig. 3
Fig. 3
The mRNA expression of regulatory-related molecules in the inductions and control groups. The relative mRNA expression levels of regulatory-related molecules (a), STAT3 gene (b) and Pias3 gene (c) in the three inductions and control groups. *P < 0.05
Fig. 4
Fig. 4
The concentrations of cytokines in the supernatant of the three induction and control groups. *P < 0.05
Fig. 5
Fig. 5
Sorted γδ T cells before and after G-CSF treatment in vivo exerted proliferation suppressive effects. a Proliferation of CFSE-labeled autologous peripheral blood CD4+ T cells (responders) co-cultured with sorted γδ T cells (effectors) before [(1)–(3)] and after [(4)–(6)] G-CSF treatment in vivo. (1), (4): negative controls (CFSE-unlabeled CD4+ T cells); (2), (5): positive controls (CFSE-labeled CD4+ T cells); (3), (6): experimental groups (CFSE-labeled CD4+ T cells + sorted γδ T cells). The data are representative of results from 10 healthy donors. (B) The scatter plot reflected the effect of sorted γδ T cells before and after G-CSF treatment in vivo on the proliferation rates of CFSE-labeled CD4+ T cells. *P < 0.05
Fig. 6
Fig. 6
Anti-TCRγδ-stimulated γδ T cells exert suppressive effects on CD4+ T cell proliferation. a The proliferation of CFSE-labeled autologous peripheral blood CD4+ T cells (responders) co-cultured with anti-TCRγδ-stimulated γδ T cells on day 9 (effectors) without [(3)–(6)]/with [(7)–(10)] TGF-β receptor inhibitor. (1) negative control (CFSE-unlabeled responders); (2) positive control (CFSE-labeled responders); (3)–(10) experimental groups; (3), (7): CFSE-labeled responders +G-CSF-induced γδ T cells; (4), (8): CFSE-labeled responders + TGF-β-induced γδ T cells; (5), (9): CFSE-labeled responders + (G-CSF + TGF-β)-induced γδ T cells; (6), (10): CFSE-labeled responders + only anti-TCRγδ stimulated γδ T cells. The data are representative of results from independent experiments of 5 healthy donors. b The bar reflected the effect of anti-TCRγδ-stimulated γδ T cells in the three inductions and control groups at day 9 of culture on the proliferation rates of CFSE-labeled CD4+ T cells. *P < 0.05
Fig. 7
Fig. 7
The cytotoxic effects of induced γδ T cells on leukemia and lymphoma cell lines. The cytotoxic effects of γδ T cells on leukemia cell lines (Molt4, HL-60, and K562) and lymphoma cell lines (Raji and Daudi) were not influenced by G-CSF, TGF-β, and G-CSF + TGF-β induction compared with the control group (P = 0.116, P = 0.538, P = 0.617, P = 0.355, and P = 0.288, respectively)
Fig. 8
Fig. 8
The correlation of γδTreg subsets in grafts and aGVHD in G-PBSCT recipients. a The proportions of γδTreg subsets in grafts in the patients who developed and did not develop aGVHD post-transplantation. b The ROC curve analysis for the optimal cutoff point of the proportion of CD27+Vδ1Tregs in grafts in prediction of aGVHD
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