Staphylococcal enterotoxin B inhibits regulatory T cells by inducing glucocorticoid-induced TNF receptor-related protein ligand on monocytes

被引:71
作者
Cardona, ID
Goleva, E
Ou, LS
Leung, DYM
机构
[1] Natl Jewish Ctr Med & Res Ctr, Dept Pediat, Denver, CO 80206 USA
[2] Chang Gung Childrens Hosp, Dept Pediat, Taoyuan, Taiwan
关键词
inflammation; superantigens; T-regulatory cells; monocyteslmacrophages; GITR-L;
D O I
10.1016/j.jaci.2005.11.037
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: Superantigens inhibit naturally occurring CD4(+)CD25(+) regulatory T-cell (nTreg) activity, yet the mechanism for this is unknown. Objective: We tested the hypothesis that staphylococcal enterotoxin B (SEB), a prototypic superantigen, inhibits the ability of nTregs to suppress T-effector cell (Teff) proliferation by an antigen-p resenting cell-dependent cell contact mechanism and the induction of glucocorticoid-induced TNF receptor-related protein ligand (GITR-L) on monocytes. Methods: Cell proliferation assays were performed on immunomagnetic-bead separated CD4(+)CD25(+), CD4(+)CD25(-) cells and CD14(+) monocytes using anti-CD3, SEB, or a neutralizing anti-GITR-L antibody for stimulation. A cytokine permeable membrane insert separating cells in culture was used to evaluate the role of cell contact. Proliferation was measured by [H-3]-thymidine incorporation or a carboxyfluorescein diacetate succinimidyl ester assay. GITR-L expression was determined by RT-PCR and immnunostaining. Results: Antigen-presenting cell contact was required for proliferation of nTregs and loss of their ability to suppress Teff proliferation as confirmed by carboxyfluorescein diacetate succinimidyl ester. At baseline, monocytes expressed no GITR-L, but after SEB stimulation, GITR-L gene and protein expression increased significantly over a period of 24 hours (P < .05). When GITR-L activity was neutralized with blocking antibody, as opposed to isotype control, nTregs suppressed Teff proliferation despite the presence of SEB (P < .05). Likewise, loss of GITR-L at 48 hours was associated with restoration of nTreg activity (P <= .05). Conclusion: Staphylococcal enterotoxin B upregulates GITR-L on monocytes and inhibits nTreg ability to suppress Teff proliferation via a cell contact interaction. Clinical implications: Prevention of GITR-L induction on monocytes by SEB may be a novel target for control of inflammation in superantigen-driven diseases such as atopic dermatitis.
引用
收藏
页码:688 / 695
页数:8
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