Transplantation Immunology Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, South Australia.
Immunol Lett. 2010 Aug 16;132(1-2):31-7. doi: 10.1016/j.imlet.2010.05.003. Epub 2010 May 24.
Interferon-gamma (IFN-gamma) is a proinflammatory cytokine that induces the proliferation of T-helper 1 cells that contribute to allograft rejection. Surprisingly, allografts transplanted in IFN-gamma deficient mice are rapidly rejected, suggesting that this cytokine has a paradoxical role in regulating alloimmune responses. Since dendritic cells (DC) play an essential role in initiating allograft rejection the effect of IFN-gamma on DC differentiation, maturation and function in vitro were investigated. DC were differentiated with IL4/GMCSF and treated with IFN-gamma at day 0 (IFN-gamma-DC(0)) or day 5 (IFN-gamma-DC(5)) during maturation and compared with untreated DC (UT-DC). Flow cytometric analysis of IFN-gamma-DC(0) demonstrated a downregulation in the DC maturation marker CD83 by 90% whereas the expression of the inhibitory molecules ILT2, ILT3 and ILT4 were upregulated. Inhibition of relB mRNA expression (79%; p=0.01) and IL-12 (97%; p=0.02) compared to UT-DC further confirmed that IFN-gamma-DC(0) were 'maturation-arrested'. Moreover, IFN-gamma-DC(0) inhibited allogeneic T cell proliferation by 33% (p=0.02) compared to UT-DC. However, induction of T cell hyporesponsiveness by IFN-gamma-DC(0) was not regulated by the generation of CD4(+)Foxp3(+) T cells nor due to IFN-gamma induced inhibitory molecules, HLA-G and IDO. In contrast, IFN-gamma-DC(5) expressed higher levels of costimulatory molecules and MHC class II compared to UT-DC and did not cause T cell hyporesponsiveness. Thus, the timing of IFN-gamma treatment of monocytes prior to their differentiation to DC is critical for generating DC that regulate T cell function. IFN-gamma may therefore play a regulatory role in alloimmunity by acting on DC precursors.
干扰素-γ（IFN-γ）是一种前炎性细胞因子，可诱导 T 辅助 1 细胞增殖，从而导致移植物排斥。令人惊讶的是，在 IFN-γ 缺陷型小鼠中移植的同种异体移植物会迅速被排斥，这表明该细胞因子在调节同种免疫反应中具有矛盾的作用。由于树突状细胞（DC）在启动同种异体移植物排斥反应中起着至关重要的作用，因此研究了 IFN-γ对 DC 体外分化、成熟和功能的影响。使用 IL4/GMCSF 将 DC 分化，并在成熟时的第 0 天（IFN-γ-DC(0)）或第 5 天（IFN-γ-DC(5)）用 IFN-γ处理，并与未经处理的 DC（UT-DC）进行比较。IFN-γ-DC(0)的流式细胞术分析显示，DC 成熟标志物 CD83 的表达下调了 90%，而抑制性分子 ILT2、ILT3 和 ILT4 的表达上调了。与 UT-DC 相比，relB mRNA 表达的抑制（79%；p=0.01）和 IL-12 的抑制（97%；p=0.02）进一步证实，IFN-γ-DC(0)处于“成熟阻滞”状态。此外，与 UT-DC 相比，IFN-γ-DC(0)抑制同种异体 T 细胞增殖 33%（p=0.02）。然而，IFN-γ-DC(0)诱导的 T 细胞低反应性不受 CD4(+)Foxp3(+)T 细胞的产生或 IFN-γ诱导的抑制性分子 HLA-G 和 IDO 的调节。相比之下，IFN-γ-DC(5)表达的共刺激分子和 MHC 类 II 水平高于 UT-DC，并且不会引起 T 细胞低反应性。因此，在单核细胞分化为 DC 之前，IFN-γ 治疗的时机对于产生调节 T 细胞功能的 DC 至关重要。IFN-γ 可能通过作用于 DC 前体细胞在同种免疫中发挥调节作用。
