Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion.
Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion.
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DOI：
10.4049/jimmunol.0901459
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发表时间：
2009-10-15
期刊：
影响因子：
--
通讯作者：
Morel PA
中科院分区：
文献类型：
--
作者：
Turner MS;Kane LP;Morel PA
致耐受性与免疫原性树突状细胞（DC）的定义仍有争议。未成熟DC已显示诱导对外来和同种异体抗原特异性的T调节细胞（Treg）。然而，我们以前曾报道，成熟的DC（G4 DC）防止自身免疫性糖尿病的发病，而不成熟的DC（GMDC）治疗无效。在本研究中，在不存在外源性细胞因子的情况下，用用高或低亲和力抗原肽脉冲的GMDC或G4 DC刺激来自BDC2.5 TCR Tg小鼠的胰岛特异性CD 4 + T细胞，并检查Treg诱导。呈现低肽剂量的GMDC和G4 DC均通过Akt/mTOR途径诱导弱TCR信号传导，导致Foxp 3 + Treg的显著扩增。此外，未脉冲的G4 DC，而不是GMDC，也诱导Treg。高剂量的肽诱导强烈的Akt/mTOR信号传导，并有利于Foxp 3 neg Th细胞的扩增。在DO11.10和OT-II TCR-Tg T细胞中也观察到Foxp 3和Akt/mTOR信号传导的负相关性，并且在不存在DC的情况下用抗CD 3/CD 28刺激重现。这些培养物中IL-6的产生与抗原剂量正相关，与Treg扩增负相关。对来自IL-6−/−小鼠的T细胞或DC的研究表明，T细胞产生的IL-6在低抗原剂量下抑制Treg诱导方面更为重要。这些研究表明，Akt/mTOR信号传导的强度（Treg vs Th诱导的关键T细胞内在决定因素）可以通过调节抗原肽的剂量来控制。此外，这在DC表型和细胞因子产生上以显性方式起作用。
The definitions of tolerogenic vs. immunogenic dendritic cells (DC) remain controversial. Immature DC have been shown to induce T regulatory cells (Treg) specific for foreign and allo-antigens. However, we have previously reported that mature DC (G4DC) prevented the onset of autoimmune diabetes whereas immature DC (GMDC) were therapeutically ineffective. In this study, islet-specific CD4+ T cells from BDC2.5 TCR Tg mice were stimulated, in the absence of exogenous cytokine, with GMDC or G4DC pulsed with high- or low-affinity antigenic peptides and examined for Treg induction. Both GMDC and G4DC presenting low peptide doses induced weak TCR signaling via the Akt/mTOR pathway, resulting in significant expansion of Foxp3+ Treg. Furthermore, unpulsed G4DC, but not GMDC, also induced Treg. High peptide doses induced strong Akt/mTOR signaling and favored the expansion of Foxp3neg Th cells. The inverse correlation of Foxp3 and Akt/mTOR signaling was also observed in DO11.10 and OT-II TCR-Tg T cells and was recapitulated with anti-CD3/CD28 stimulation in the absence of DC. IL-6 production in these cultures correlated positively with antigen dose and inversely with Treg expansion. Studies with T cells or DC from IL-6−/− mice revealed that IL-6 production by T cells was more important in the inhibition of Treg induction at low antigen doses. These studies indicate that strength of Akt/mTOR signaling, a critical T cell intrinsic determinant for Treg vs Th induction, can be controlled by adjusting the dose of antigenic peptide. Furthermore, this operates in a dominant fashion over DC phenotype and cytokine production.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
15.3
作者：
Apostolou, I;von Boehmer, H
通讯作者：
von Boehmer, H
影响因子：
4.4
作者：
Kang, Hee-Kap;Liu, Michael;Datta, Syamal K.
通讯作者：
Datta, Syamal K.
影响因子：
5.5
作者：
Feili-Hariri, M;Falkner, DH;Morel, PA
通讯作者：
Morel, PA
影响因子：
30.5
作者：
Kishimoto, H;Sprent, J
通讯作者：
Sprent, J