2020年10月，吴德沛教授、刘跃均教授研究团队在免疫学权威期刊Frontiers in Immunology以研究论文形式发表了关于慢性移植物抗宿主病（cGVHD）的最新研究成果“IL-Y Aggravates Murine Chronic Graft-versus-HostDisease by Enhancing T and B cell Responses”。
白细胞介素-12（IL-12）家族细胞因子具有多效性，在多种免疫应答中发挥重要作用。目前，这个细胞因子家族有6种细胞因子，包括IL-12 (p35/p40)、IL-23 (p19/p40)、IL-27 (p28/EBI3)、IL-35 (p35/EBI3)、IL-39 (p19/EBI3)，以及IL-Y (p28/p40)（合成的）。近期研究发现，IL-12家族IL-27α链p28和IL-12/IL-23β链p40的免疫沉淀反应后的Western blot实验表明，p28和p40之间可能通过二硫键形成稳定的联系，并且研究发现其在自身免疫性疾病、感染性疾病及恶性肿瘤中可能发挥了重要的免疫调控功能，但IL-Y在cGVHD中的作用机制尚不清楚。
课题组研究发现，IL-Y促进cGVHD的发生发展。在cGVHD发生早期，IL-Y显著抑制调节性T（Treg）细胞的增殖分化，并且IL-Y过表达质粒以及重组蛋白能显著促进cGVHD靶器官中供体T、B细胞的活化及炎症因子TNF-α的分泌。进一步研究发现，IL-Y通过IL-27Rα促进CD4+T细胞和CD8+T细胞分泌细胞因子TNF-α。另外，IL-Y还能促进ICOS+Tfh增殖分化，提高Tfh细胞促进B细胞分化为生发中心B细胞、浆细胞能力，以及提高B细胞产生自身抗体的能力等共同发挥作用。尽管IL-Y促进cGVHD的详细机制需要进一步探索，但我们的结果为IL-Y在cGVHD中的作用以及针对IL-27Rα信号转导的可能治疗策略提供了新的思路。
原文摘要：IL-Y, a synthetic member ofIL-12 cytokine family, was found to exert potent immunosuppressive effects byinhibiting the differentiation and activation of Th1 and Th17 cells. However,the role of IL-Y in the development of chronic graft-versus-host disease(cGVHD) remains unknown. Here, using murine models of scleroderma-like andlupus-like cGVHD, we examined the function of IL-Y in the pathogenesis of cGVHD by hydrodynamically injectingminicircle-IL-Y expressing plasmids (MC IL-Y). In contrast with the reportedimmune suppressive function of IL-Y, administration of MC IL-Y enhanced cGVHDseverity reflected by deteriorated multi-organ pathologic damages. Inlupus-like cGVHD model, urine protein and the serum anti-dsDNA antibody (IgG)were significantly upregulated by IL-Y treatment. Further study demonstratedthat IL-Y impacts both donor T and B cell response. In T cells, IL-Y inhibitedthe generation of CD4+Foxp3+ regulator T (Treg) cells during the development ofcGVHD. IL-Y may also increase the infiltration of pathogenic TNF-α producingCD4+ and CD8+ T cells through IL-27Rα in recipient spleens, as this effect wasdiminished in IL-27Rα deficient T cells. Moreover, IL-Y enhanced the differentiation of ICOS+ T follicularhelper (Tfh) cells. In B cells, the percentage of germinal center (GC) B cells in recipient spleens wassignificantly upregulated by MC IL-Y plasmids administration. The levels of co-stimulatorymolecules, MHC-II and CD86, on B cells were also enhanced by IL-Y expression.Taken together, our data indicated that IL-Y promoted the process of cGVHD byactivating pathogenic T and B cells.
