Akieda Yuki, Wakamatsu Ei, Nakamura Tomoe, Ishida Yasuo, Ogawa Shuhei, Abe Ryo
Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan; and.
Department of Pathology, Teikyo University Chiba Medical Center, Chiba 299-0111, Japan.
J Immunol. 2015 May 1;194(9):4162-74. doi: 10.4049/jimmunol.1402591. Epub 2015 Mar 30.
In patients receiving allogeneic hematopoietic cell transplantation, chronic graft-versus-host disease (cGVHD) remains a frequent complication and resembles autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis. Our previous work demonstrated the critical role of CD28 costimulation of donor T cells for GVHD induction. In this study, we investigate the role of CD28 costimulation of host T cells in cGVHD. CD28-intact mice as hosts showed systemic lupus erythematosus-type cGVHD, whereas CD28-deficient mice developed a distinct phenotype of cGVHD, with fibrotic damage in skin and internal organs, resembling systemic sclerosis. This phenotype was due to a lack of signaling through the C-terminal proline-rich motif within host CD28's cytoplasmic tail, a motif previously shown to be required for development of regulatory T cells (Tregs) and function of conventional T cells. Adoptive transfer experiments demonstrated that a defect in host CD4(+)CD25(+) Tregs, but not in conventional T cells, was responsible for disease phenotype. Host Treg deficiency altered the cytokine pattern of donor CD4(+) T cells and the Ag specificity of autoantibodies, and these might lead to phenotypic change. Thus, host CD28 signaling controlled the pathogenesis of cGVHD through effects on host Tregs, whose status impacts qualitatively on the allogeneic immune responses.
在接受异基因造血细胞移植的患者中，慢性移植物抗宿主病（cGVHD）仍然是一种常见的并发症，并且类似于自身免疫性疾病，如系统性红斑狼疮和系统性硬化症。我们之前的研究表明，供体T细胞的CD28共刺激在GVHD诱导中起关键作用。在本研究中，我们调查宿主T细胞的CD28共刺激在cGVHD中的作用。作为宿主的CD28完整小鼠表现出系统性红斑狼疮型cGVHD，而CD28缺陷小鼠则发展出一种独特的cGVHD表型，皮肤和内脏器官出现纤维化损伤，类似于系统性硬化症。这种表型是由于宿主CD28胞质尾部富含脯氨酸的C末端基序缺乏信号传导，该基序先前已被证明是调节性T细胞（Tregs）发育和常规T细胞功能所必需的。过继转移实验表明，宿主CD4(+)CD25(+) Tregs缺陷而非常规T细胞缺陷是导致疾病表型的原因。宿主Treg缺陷改变了供体CD4(+) T细胞的细胞因子模式和自身抗体的抗原特异性，而这些可能导致表型改变。因此，宿主CD28信号传导通过对宿主Tregs的影响控制了cGVHD的发病机制，Tregs的状态对异基因免疫反应有定性影响。
