Zou W, Borvak J, Marches F, Wei S, Galanaud P, Emilie D, Curiel T J
Baylor Institute for Immunology Research, Dallas, TX 75204. Institut Paris-Sud Sur Les Cytokines, Institut National de la Santé et de la Recherche Médicale, Clamart, France.
J Immunol. 2000 Oct 15;165(8):4388-96. doi: 10.4049/jimmunol.165.8.4388.
Monocyte-derived dendritic cells (MDDCs) activate naive T lymphocytes to induce adaptive immunity, effecting Th1 polarization through IL-12. However, little is known about other potential DC Th1 polarizing mechanisms, or how T cell polarization may be affected by DCs differentiating in, or exposed to, a proinflammatory environment. Macrophages (MPhis) are DC precursors abundant in inflamed tissues, lymph nodes, and tumors. Thus we studied the T cell-activating and -polarizing properties of MPhi-derived DCs (PhiDCs). Monocytes were cultured in MPhi-CSF (M-CSF) to produce MPhis, which were then differentiated into DCs following culture with GM-CSF plus IL-4. PhiDCs activated a significant allogeneic MLR and were significantly better than MDDCs in activating T cells with superantigen. Most strikingly, PhiDCs elicited up to 9-fold more IFN-gamma from naive or Ag-specific T cells compared with MDDCs (with equivalent IL-4 secretion), despite producing up to 9-fold less IL-12. Neutralization of MDDC, but not PhiDC IL-12 significantly inhibited T cell IFN-gamma induction. PhiDCs produced up to 12-fold more beta-chemokines (macrophage-inflammatory protein-1alpha, -1beta, and RANTES) than MDDCs. Ab blockade of CCR5, but not CXC chemokine receptor 4, inhibited T cell IFN-gamma induction by PhiDCs significantly greater than by MDDCs. Thus DCs differentiating from MPhis induce T cell IFN-gamma through beta-chemokines with little or no requirement for IL-12. Myeloid DCs arising from distinct precursor cells may have differing properties, including different mechanisms of Th1 polarization. These data are the first reports of IFN-gamma induction through chemokines by DCs.
单核细胞衍生的树突状细胞（MDDC）激活初始T淋巴细胞以诱导适应性免疫，通过白细胞介素-12实现Th1极化。然而，对于其他潜在的树突状细胞Th1极化机制，或者在促炎环境中分化或暴露于其中的树突状细胞如何影响T细胞极化，我们了解甚少。巨噬细胞（MPhi）是炎症组织、淋巴结和肿瘤中丰富的树突状细胞前体。因此，我们研究了MPhi衍生的树突状细胞（PhiDC）的T细胞激活和极化特性。将单核细胞培养在MPhi-CSF（M-CSF）中以产生MPhi，然后在用GM-CSF加IL-4培养后将其分化为树突状细胞。PhiDC激活了显著的同种异体混合淋巴细胞反应（MLR），并且在用超抗原激活T细胞方面明显优于MDDC。最引人注目的是，与MDDC相比（IL-4分泌量相当），PhiDC从初始或抗原特异性T细胞中诱导产生的干扰素-γ多高达9倍，尽管其白细胞介素-12的产生量少至9倍。中和MDDC而非PhiDC的白细胞介素-12可显著抑制T细胞干扰素-γ的诱导。PhiDC产生的β趋化因子（巨噬细胞炎性蛋白-1α、-1β和RANTES）比MDDC多高达12倍。抗体阻断CCR5而非CXC趋化因子受体4对PhiDC诱导T细胞干扰素-γ的抑制作用明显大于对MDDC的抑制作用。因此，从MPhi分化而来的树突状细胞通过β趋化因子诱导T细胞产生干扰素-γ，对白细胞介素-12的需求很少或不需要。源自不同前体细胞的髓样树突状细胞可能具有不同的特性，包括Th1极化的不同机制。这些数据是关于树突状细胞通过趋化因子诱导干扰素-γ的首批报道。
