Comprehensive Analysis of the Activation and Proliferation Kinetics and Effector Functions of Human Lymphocytes, and Antigen Presentation Capacity of Antigen-Presenting Cells in Xenogeneic Graft-Versus-Host Disease
Comprehensive Analysis of the Activation and Proliferation Kinetics and Effector Functions of Human Lymphocytes, and Antigen Presentation Capacity of Antigen-Presenting Cells in Xenogeneic Graft-Versus-Host Disease
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DOI：
10.1016/j.bbmt.2018.04.016
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发表时间：
2018-08-01
影响因子：
4.3
通讯作者：
Kanda, Yoshinobu
中科院分区：
文献类型：
--
作者：
Kawasaki, Yasufumi;Sato, Kazuya;Kanda, Yoshinobu
高免疫缺陷小鼠的异种移植物抗宿主病(GVHD)模型目前正在全球范围内用于研究体内人类对外来抗原的免疫反应。然而，CD4(+)和CD8(+)T细胞以及供者/宿主造血和非造血抗原提呈细胞(APC)在GVHD的诱导和发展中的单独作用还没有得到充分的研究。在本研究中，我们使用非肥胖糖尿病/SHI-SCID-IL2RG(Null)小鼠，在异种GVHD模型中，全面研究了人T细胞的免疫应答和供体/宿主造血和非造血APC的抗原提呈能力。CD4(+)T细胞和CD8(+)T细胞分别介导潜在的致死性移植物抗宿主病。除了炎性细胞因子的产生，CD4(+)T细胞也支持CD8(+)T细胞的激活和增殖。利用骨髓嵌合体，我们证明了宿主造血型而不是非造血型APC在CD4(+)T细胞介导的GVHD的发展中起着关键作用。在早期移植物抗宿主病中，我们在记忆中检测到两种不同的CD4(+)T细胞。一个群体在主要组织相容性复合体抗原(MHC)(+/+)小鼠中高度激活和增殖，而在MHC-/-小鼠中则不是，这表明同种异体反应性T细胞。与宿主MHC表达无关，其他人群表现出较低的活化和缓慢的增殖状态，并且与较高的凋亡易感性相关，表明非同种异体反应性T细胞在动态平衡驱动的增殖中。这些观察结果与异基因造血干细胞移植后供者T细胞反应有关。我们的发现有助于更好地了解人源化小鼠的免疫生物学，并支持开发预防和治疗移植物抗宿主病的新方案。(C)2018年美国血液和骨髓移植学会。
Xenogeneic graft-versus-host disease (GVHD) models in highly immunodeficient mice are currently being used worldwide to investigate human immune responses against foreign antigens in vivo. However, the individual roles of CD4(+) and CD8(+) T cells, and donor/host hematopoietic and nonhematopoietic antigen-presenting cells (APCs) in the induction and development of GVHD have not been fully investigated. In the present study, we comprehensively investigated the immune responses of human T cells and the antigen presentation capacity of donor/host hematopoietic and nonhematopoietic APCs in xenogeneic GVHD models using nonobese diabetic/Shi-scid-IL2rg(null) mice. CD4(+) T cells and, to a lesser extent, CD8(+) T cells individually mediated potentially lethal GVHD. In addition to inflammatory cytokine production, CD4(+) T cells also supported the activation and proliferation of CD8(+) T cells. Using bone marrow chimeras, we demonstrated that host hematopoietic, but not non-hematopoietic, APCs play a critical role in the development of CD4(+) T cell-mediated GVHD. During early GVHD, we detected 2 distinct populations in memory CD4(+) T cells. One population was highly activated and proliferated in major histocompatibility complex antigen (MHC)(+/+) mice but not in MHC-/- mice, indicating alloreactive T cells. The other population showed a less activated and slowly proliferative status regardless of host MHC expression, and was associated with higher susceptibility to apoptosis, indicating non-alloreactive T cells in homeostasis-driven proliferation. These observations are clinically relevant to donor T cell response after allogeneic hematopoietic stem cell transplantation. Our findings provide a better understanding of the immunobiology of humanized mice and support the development of novel options for the prevention and treatment for GVHD. (C) 2018 American Society for Blood and Marrow Transplantation.