Ohshima Y, Tanaka Y, Tozawa H, Takahashi Y, Maliszewski C, Delespesse G
University of Montreal, Centre de Recherche Louis-Charles Simard, Notre Dame Hospital, Quebec, Canada.
J Immunol. 1997 Oct 15;159(8):3838-48.
OX40 ligand (OX40L), a member of the TNF family, was shown to be capable of signaling both the cells on which it is expressed and those expressing OX40, its cognate receptor. Here we show that OX40L is expressed on dendritic cells (DC), the most efficient APC to prime naive T cells. The expression and the functional activity of OX40L were examined by means of mAbs used to stain or cross-link OX40L on 1) freshly isolated human blood DC (bDC) and 2) monocyte-derived DC at different stages of differentiation. These were derived from monocytes cultured either with IL-4 and granulocyte-macrophage CSF (IL-4-Mo-DC) or with IL-4 and granulocyte-macrophage CSF plus TNF-alpha. Both types of Mo-DC expressed OX40L after stimulation through CD40; ligation of OX40L on activated IL-4-Mo-DC enhanced by 4- to 35-fold their cytokine production (TNF-alpha, IL-12 p40, IL-1 beta, and IL-6) and increased CD80, CD86, CD54, and CD40 expression. Stimulation of activated IL-4-Mo-DC through OX40L strikingly enhanced their maturation as evidenced by CD83 up-regulation, CD115 (CSF-1R) down-regulation, and typical morphologic changes. OX40L was constitutively expressed on a subset of bDC, and its ligation slightly enhanced CD40L-stimulated IL-12 production. OX40L was down-regulated after overnight culture and spontaneously reexpressed on a subset of mature bDC (CD83high, CD33high, CD11chigh, CD5+). Thus, the expression of OX40L on DC suggests a physiologic role of this molecule during T cell priming by virtue of its ability to costimulate both T cell and DC activation and differentiation.
OX40配体（OX40L）是肿瘤坏死因子（TNF）家族的一员，已证明它能够向表达自身的细胞以及表达其同源受体OX40的细胞传递信号。在此我们发现，OX40L表达于树突状细胞（DC），即启动初始T细胞最有效的抗原呈递细胞（APC）。我们通过单克隆抗体（mAbs）来检测OX40L的表达及功能活性，这些单克隆抗体用于对以下两种细胞上的OX40L进行染色或交联：1）新鲜分离的人血DC（bDC）；2）处于不同分化阶段的单核细胞衍生DC。这些单核细胞衍生DC由单核细胞培养而来，培养条件分别为：白细胞介素-4（IL-4）和粒细胞巨噬细胞集落刺激因子（GM-CSF）（IL-4-Mo-DC），或IL-4、GM-CSF加肿瘤坏死因子-α（TNF-α）。两种类型的Mo-DC在通过CD40刺激后均表达OX40L；激活的IL-4-Mo-DC上OX40L的连接使其细胞因子产生（TNF-α、IL-12 p40、IL-1β和IL-6）增强4至35倍，并增加CD80、CD86、CD54和CD40的表达。通过OX40L刺激激活的IL-4-Mo-DC显著增强其成熟，这可通过CD83上调、CD115（CSF-1R）下调以及典型的形态学变化得以证明。OX40L在一部分bDC上组成性表达，其连接略微增强了CD40L刺激的IL-12产生。过夜培养后OX40L表达下调，并在一部分成熟bDC（CD83高、CD33高、CD11c高、CD5 +）上自发重新表达。因此，DC上OX40L的表达表明该分子在T细胞启动过程中具有生理作用，因为它能够共刺激T细胞以及DC的激活和分化。
