Soroosh Pejman, Ine Shouji, Sugamura Kazuo, Ishii Naoto
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai 980-8575, Japan.
J Immunol. 2006 May 15;176(10):5975-87. doi: 10.4049/jimmunol.176.10.5975.
Signals through the OX40 costimulatory receptor on naive CD4 T cells are essential for full-fledged CD4 T cell activation and the generation of CD4 memory T cells. Because the ligand for OX40 is mainly expressed by APCs, including activated B cells, dendritic cells, and Langerhans cells, the OX40-OX40 ligand (OX40L) interaction has been thought to participate in T cell-APC interactions. Although several reports have revealed the expression of OX40L on T cells, the functional significance of its expression on them is still unclear. In this study, we demonstrate that Ag stimulation induced an increase in the surface expression and transcript levels of OX40L in CD4 T cells. Upon contact with OX40-expressing T cells, the cell surface expression of OX40L on CD4 T cells was markedly down-regulated, suggesting that OX40-OX40L binding occurs through a novel T cell-T cell interaction. To investigate the function of this phenomenon, we examined the proliferative response and survival of OX40L-deficient CD4 T cells when challenged with Ag. In vitro studies demonstrated markedly less CD3-induced proliferation of OX40L-deficient CD4 T cells compared with wild-type CD4 T cells. When using TCR transgenic CD4 T cells upon Ag stimulation, survival of OX40L-deficient T cells was impaired. Furthermore, we show that upon antigenic stimulation, fewer OX40L-deficient CD4 T cells than wild-type cells survived following transfer into wild-type and sublethally irradiated recipient mice. Taken together, our findings indicate that OX40L-expressing T cells have an autonomous machinery that provides OX40 signals through a T cell-T cell circuit, creating an additional mechanism for sustaining CD4 T cell longevity.
初始CD4 T细胞上通过OX40共刺激受体传导的信号对于成熟的CD4 T细胞激活以及CD4记忆T细胞的产生至关重要。由于OX40的配体主要由包括活化B细胞、树突状细胞和朗格汉斯细胞在内的抗原呈递细胞（APC）表达，因此OX40-OX40配体（OX40L）相互作用被认为参与了T细胞与APC的相互作用。尽管有几份报告揭示了OX40L在T细胞上的表达，但其在T细胞上表达的功能意义仍不清楚。在本研究中，我们证明抗原刺激可诱导CD4 T细胞中OX40L的表面表达和转录水平增加。与表达OX40的T细胞接触后，CD4 T细胞上OX40L的细胞表面表达明显下调，这表明OX40-OX40L结合是通过一种新型的T细胞-T细胞相互作用发生的。为了研究这种现象的功能，我们检测了用抗原攻击时OX40L缺陷型CD4 T细胞的增殖反应和存活情况。体外研究表明，与野生型CD4 T细胞相比，OX40L缺陷型CD4 T细胞的CD3诱导增殖明显减少。当在抗原刺激时使用TCR转基因CD4 T细胞时，OX40L缺陷型T细胞的存活受到损害。此外，我们表明，在抗原刺激后，转入野生型和亚致死剂量照射的受体小鼠体内后，存活的OX40L缺陷型CD4 T细胞比野生型细胞少。综上所述，我们的研究结果表明，表达OX40L的T细胞具有一种自主机制，可通过T细胞-T细胞回路提供OX40信号，从而为维持CD4 T细胞的长寿创造了一种额外的机制。
