SHIP-Deficient Dendritic Cells, Unlike Wild Type Dendritic Cells, Suppress T Cell Proliferation via a Nitric Oxide-Independent Mechanism
SHIP-Deficient Dendritic Cells, Unlike Wild Type Dendritic Cells, Suppress T Cell Proliferation via a Nitric Oxide-Independent Mechanism
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DOI：
10.1371/journal.pone.0021893
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发表时间：
2011-07-06
期刊：
影响因子：
3.7
通讯作者：
Krystal, Gerald
中科院分区：
文献类型：
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作者：
Antignano, Frann;Hamilton, Melisa;Krystal, Gerald
背景：树突状细胞（Dendritic cells，DCs）不仅在激活免疫细胞中起重要作用，而且还能抑制免疫细胞。我们最近研究了SHIP在小鼠DC中在免疫细胞活化方面的作用，发现TLR激动剂刺激的SHIP-/- GM-CSF衍生的DC（GM-DC）在活化T细胞增殖方面的能力远低于野生型（WT，SHIP+/+）GM-DC。这很可能是因为SHIP-/- GM-DCs在TLR刺激后不能上调MHCII和/或共刺激受体。然而，船舶在DC诱导的T细胞抑制的作用没有investigated.Methodology/主要调查结果：在这项研究中，我们研究了船舶的作用，在DC诱导的T细胞抑制共培养WT和船舶-/-小鼠的DC，在不同的条件下或分离的脾脏，与α CD 3 + α CD 28激活的WT T细胞，并确定了不同的DC亚群的相对抑制能力。我们发现，与不抑制体外T细胞增殖的SHIP+/+和-/-脾或Flt 3L衍生的DC相反，SHIP+/+和-/-GM-DC都能够有效地抑制T细胞增殖。然而，WT GM-DC抑制似乎至少部分地由一氧化氮（NO）产生介导，而SHIP-/-GM-DC表达高水平的谷胱甘肽转移酶1并且不产生NO。在详尽的研究以确定SHIP-/-DC介导的抑制的机制之后，我们可以得出结论，细胞-细胞接触是必需的，并且该机制可能与它们的相对不成熟有关，结论：SHIP +/+和-/-GM-DCs均能抑制T细胞增殖，但其作用机制不同。WT GM-DCs至少部分地通过IFN γ诱导的NO产生而抑制，而SHIP-/- GM-DCs不产生NO，并且抑制仅在接触被阻止时才能减轻。
Background: Dendritic cells (DCs) not only play a crucial role in activating immune cells but also suppressing them. We recently investigated SHIP's role in murine DCs in terms of immune cell activation and found that TLR agonist-stimulated SHIP-/- GM-CSF-derived DCs (GM-DCs) were far less capable than wild type (WT, SHIP+/+) GM-DCs at activating T cell proliferation. This was most likely because SHIP-/- GM-DCs could not up-regulate MHCII and/or co-stimulatory receptors following TLR stimulation. However, the role of SHIP in DC-induced T cell suppression was not investigated.Methodology/Principal Findings: In this study we examined SHIP's role in DC-induced T cell suppression by co-culturing WT and SHIP-/- murine DCs, derived under different conditions or isolated from spleens, with alpha CD3+ alpha CD28 activated WT T cells and determined the relative suppressive abilities of the different DC subsets. We found that, in contrast to SHIP+/+ and -/- splenic or Flt3L-derived DCs, which do not suppress T cell proliferation in vitro, both SHIP+/+ and -/- GM-DCs were capable of potently suppressing T cell proliferation. However, WT GM-DC suppression appeared to be mediated, at least in part, by nitric oxide (NO) production while SHIP-/- GM-DCs expressed high levels of arginase 1 and did not produce NO. Following exhaustive studies to ascertain the mechanism of SHIP-/- DC-mediated suppression, we could conclude that cell-cell contact was required and the mechanism may be related to their relative immaturity, compared to SHIP+/+ GM-DCs.Conclusions: These findings suggest that although both SHIP+/+ and -/- GM-DCs suppress T cell proliferation, the mechanism(s) employed are different. WT GM-DCs suppress, at least in part, via IFN gamma-induced NO production while SHIP-/- GM-DCs do not produce NO and suppression can only be alleviated when contact is prevented.