Physiology and Experimental Medicine Research Program, Hospital for Sick Children, Toronto, ON, Canada.
Eur J Immunol. 2010 Apr;40(4):1022-35. doi: 10.1002/eji.200939782.
DC apoptosis has been observed in patients with cancer and sepsis, and defects in DC apoptosis have been implicated in the development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses, are unclear. In this study, we showed that immature viable DC have the ability to uptake apoptotic DC as well as necrotic DC without it being recognized as an inflammatory event by immature viable DC. However, the specific uptake of apoptotic DC converted immature viable DC into tolerogenic DC, which were resistant to LPS-induced maturation. These tolerogenic DC secreted increased levels of TGF-beta1, which induced differentiation of naïve T cells into Foxp3(+) Treg. Furthermore, induction of Treg differentiation only occurred upon uptake of apoptotic DC and not apoptotic splenocytes by viable DC, indicating that it is specifically the uptake of apoptotic DC that gives viable immature DC the potential to induce Foxp3(+) Treg. Taken together, these findings identify uptake of apoptotic DC by viable immature DC as an immunologically tolerogenic event.
在癌症和脓毒症患者中已经观察到树突状细胞凋亡，并且树突状细胞凋亡缺陷与自身免疫性疾病的发展有关。然而，树突状细胞凋亡如何影响免疫反应的机制尚不清楚。在这项研究中，我们表明，未成熟的有活力的树突状细胞能够摄取凋亡的树突状细胞和坏死的树突状细胞，而未成熟的有活力的树突状细胞不会将其识别为炎症事件。然而，凋亡的树突状细胞的特异性摄取将未成熟的有活力的树突状细胞转化为耐受性树突状细胞，后者对 LPS 诱导的成熟具有抗性。这些耐受性树突状细胞分泌了更高水平的 TGF-β1，诱导幼稚 T 细胞分化为 Foxp3+Treg。此外，Treg 分化的诱导仅发生在有活力的未成熟树突状细胞摄取凋亡的树突状细胞而不是凋亡的脾细胞时，表明正是凋亡的树突状细胞的摄取赋予了有活力的未成熟树突状细胞诱导 Foxp3+Treg 的潜力。总之，这些发现确定了有活力的未成熟树突状细胞摄取凋亡的树突状细胞是一种免疫耐受事件。
