The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
PLoS One. 2011;6(7):e21893. doi: 10.1371/journal.pone.0021893. Epub 2011 Jul 6.
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 αCD3+ αCD28 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.
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 IFNγ-induced NO production while SHIP-/- GM-DCs do not produce NO and suppression can only be alleviated when contact is prevented.
树突状细胞 (DC) 不仅在激活免疫细胞方面发挥着关键作用，而且还具有抑制作用。我们最近研究了 SHIP 在小鼠 DC 中的作用，涉及免疫细胞的激活，发现 TLR 激动剂刺激的 SHIP-/- GM-CSF 衍生的 DC（GM-DC）在激活 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-DC 在 TLR 刺激后不能上调 MHCII 和/或共刺激受体。然而，SHIP 在 DC 诱导的 T 细胞抑制中的作用尚未得到研究。
方法/主要发现：在这项研究中，我们通过共培养 WT 和 SHIP-/- 鼠 DC，研究了 SHIP 在 DC 诱导的 T 细胞抑制中的作用，这些 DC 是在不同条件下衍生的或从脾脏中分离出来的，与 αCD3+αCD28 激活的 WT T 细胞共培养，并确定了不同 DC 亚群的相对抑制能力。我们发现，与 SHIP+/+ 和 -/- 脾脏或 Flt3L 衍生的 DC 不同，后者在体外不能抑制 T 细胞增殖，SHIP+/+ 和 -/- GM-DC 均能够强烈抑制 T 细胞增殖。然而，WT GM-DC 的抑制似乎至少部分是通过一氧化氮 (NO) 产生介导的，而 SHIP-/- GM-DC 表达高水平的精氨酸酶 1 并且不产生 NO。在进行了详尽的研究以确定 SHIP-/- DC 介导的抑制的机制后，我们可以得出结论，细胞间接触是必需的，并且该机制可能与其相对于 WT GM-DC 的相对不成熟有关。
这些发现表明，尽管 SHIP+/+ 和 -/- GM-DC 都抑制 T 细胞增殖，但所采用的机制不同。WT GM-DC 抑制，至少部分是通过 IFNγ 诱导的 NO 产生介导的，而 SHIP-/- GM-DC 不产生 NO，并且只有在防止接触时才能缓解抑制。
