Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function.
Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function.
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DOI：
10.4049/jimmunol.1502181
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发表时间：
2017-07-01
期刊：
影响因子：
--
通讯作者：
Cao X
中科院分区：
文献类型：
--
作者：
Leigh ND;O'Neill RE;Du W;Chen C;Qiu J;Ashwell JD;McCarthy PL;Chen GL;Cao X
异基因造血细胞移植（allo-HCT）是一种治疗血液病和免疫病的潜在方法。然而，移植物抗宿主病（GVHD）可能发展时，供体来源的T细胞识别和损伤遗传上不同的正常宿主组织。除了T细胞受体信号传导外，共刺激途径也参与T细胞活化。CD 27是在T细胞上表达的TNF受体家族成员，其配体CD 70在APC上表达。CD 27/CD 70共刺激途径被证明对病毒感染模型中的T细胞功能和存活至关重要。然而，该途径在allo-HCT中的作用以前是未知的。在这项研究中，我们研究了其在GVHD发病机制中的作用。令人惊讶的是，在allo-HCT后CD 70的抗体阻断显著增加GVHD。有趣的是，虽然供体T细胞或BM来源的CD 70在GVHD中不起作用，但宿主来源的CD 70抑制GVHD，因为CD 70-/-宿主显示出显著增加的GVHD。这通过与WT宿主相比存活率降低、体重减轻更严重和组织病理学损伤增加来证明。此外，CD 70-/-宿主具有较高水平的促炎细胞因子TNF-α、IFN-γ、IL-2和IL-17。此外，与WT宿主相比，供体CD 4+和CD 8+效应T细胞的积累在CD 70-/-宿主中增加。机制分析表明，宿主造血细胞表达的CD 70参与同种异体反应性T细胞凋亡和扩增的控制。总之，我们的研究结果表明，宿主CD 70通过促进供体T细胞凋亡和抑制供体效应T细胞的扩增，作为同种异体T细胞应答的独特负调节因子。
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) may develop when donor-derived T cells recognize and damage genetically distinct normal host tissues. In addition to T cell receptor signaling, co-stimulatory pathways are involved in T cell activation. CD27 is a TNF receptor family member expressed on T cells and its ligand, CD70, is expressed on APCs. The CD27/CD70 co-stimulatory pathway was shown to be critical for T cell function and survival in viral infection models. However, the role of this pathway in allo-HCT is previously unknown. In this study, we have examined its contribution in GVHD pathogenesis. Surprisingly, antibody blockade of CD70 following allo-HCT significantly increases GVHD. Interestingly, while donor T cell- or BM-derived CD70 plays no role in GVHD, host-derived CD70 inhibits GVHD as CD70-/- hosts show significantly increased GVHD. This is evidenced by reduced survival, more severe weight loss, and increased histopathologic damage compared to WT hosts. In addition, CD70-/- hosts have higher levels of proinflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-17. Moreover, accumulation of donor CD4+ and CD8+ effector T cells is increased in CD70-/- versus WT hosts. Mechanistic analyses suggest that CD70 expressed by host hematopoietic cells is involved in the control of alloreactive T cell apoptosis and expansion. Together, our findings demonstrate that host CD70 serves as a unique negative regulator of allogeneic T cell response by contributing to donor T cell apoptosis and inhibiting expansion of donor effector T cells.
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影响因子：
15.3
作者：
Hendricks, J;Xiao, YL;Borst, J
通讯作者：
Borst, J
影响因子：
20.3
作者：
Beilhack, A;Schulz, S;Negrin, RS
通讯作者：
Negrin, RS
供体型CD4（+）CD25（+）调节性T细胞在同种异体骨髓移植后抑制致命的急性移植物抗宿主疾病。
影响因子：
15.3
作者：
Hoffmann, Petra;Ermann, Joerg;Edinger, Matthias;Fathman, C Garrison;Strober, Samuel
通讯作者：
Strober, Samuel
DOI：
10.4049/jimmunol.1500668
发表时间：
2015-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Du W;Leigh ND;Bian G;O'Neill RE;Mei L;Qiu J;Chen GL;Hahn T;Liu H;McCarthy PL;Cao X
通讯作者：
Cao X
DOI：
10.4049/jimmunol.1200858
发表时间：
2012-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fulton LM;Carlson MJ;Coghill JM;Ott LE;West ML;Panoskaltsis-Mortari A;Littman DR;Blazar BR;Serody JS
通讯作者：
Serody JS