Jacquemin Clément, Schmitt Nathalie, Contin-Bordes Cécile, Liu Yang, Narayanan Priya, Seneschal Julien, Maurouard Typhanie, Dougall David, Davizon Emily Spence, Dumortier Hélène, Douchet Isabelle, Raffray Loïc, Richez Christophe, Lazaro Estibaliz, Duffau Pierre, Truchetet Marie-Elise, Khoryati Liliane, Mercié Patrick, Couzi Lionel, Merville Pierre, Schaeverbeke Thierry, Viallard Jean-François, Pellegrin Jean-Luc, Moreau Jean-François, Muller Sylviane, Zurawski Sandy, Coffman Robert L, Pascual Virginia, Ueno Hideki, Blanco Patrick
University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France.
Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
Immunity. 2015 Jun 16;42(6):1159-70. doi: 10.1016/j.immuni.2015.05.012. Epub 2015 Jun 9.
Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS(+) blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4(+) T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.
滤泡辅助性T细胞（Tfh）活性增加在系统性红斑狼疮（SLE）中起主要致病作用。然而，导致SLE中Tfh细胞反应异常的机制仍不清楚。在此我们表明，OX40配体（OX40L）-OX40轴促成了SLE中异常的Tfh反应。在成年和儿童SLE患者的血液及炎症组织中，髓系抗原呈递细胞（APC）而非B细胞表达OX40L。循环中表达OX40L的髓系APC频率与SLE疾病活动度及ICOS(+)血液Tfh细胞频率呈正相关。OX40信号促使初始和记忆性CD4(+) T细胞表达多种Tfh细胞分子，且足以诱导它们成为功能性B细胞辅助细胞。含RNA的免疫复合物通过TLR7激活诱导髓系APC表达OX40L。我们的研究为将OX40L-OX40轴作为SLE的一种治疗方式提供了理论依据。
