Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD
Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD
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DOI：
10.1182/blood-2007-01-067249
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发表时间：
2007-06-01
期刊：
影响因子：
20.3
通讯作者：
Hill, Geoffrey R.
中科院分区：
文献类型：
--
作者：
MacDonald, Kelli P. A.;Kuns, Rachel D.;Hill, Geoffrey R.
抗原提呈细胞（APC）是引发移植物抗宿主病（GVHD）的关键细胞，但其亚群和分子机制尚不清楚。由于树突状细胞（DC）是最有效的APC，并且NF-kB/Rel家族成员ReIB与DC成熟和有效的APC功能相关，因此我们研究了它们在GVHD中的作用。在全身照射的4小时内，ReIB核转位增加并限于宿主APC隔室内的CD 11 c（hi）DC。此外，在移植后第二周重建的CD 11 C（hi）供体DC的瞬时消耗导致GVHD严重程度的瞬时降低。通过使用ReIB-/-骨髓嵌合体作为移植受体或ReIB-/-供体骨髓，我们证明GVHD的诱导和维持严重依赖于宿主和供体APC内的这种转录因子。重要的是，APC内的ReIB是供体辅助性T细胞1型（Th 1）效应子扩增和随后的同种异体反应性所必需的，但不是供体FoxP 3（+）调节性T细胞的外周扩增或功能所必需的。这些数据表明，靶向抑制APC内的核ReIB易位代表了一种有吸引力的治疗策略，以在Th 1介导的组织损伤的情况下解离效应和调节T细胞功能。
Antigen-presenti n g cells (APCs) are critical for the initiation of graft-versus-host disease (GVHD), although the responsible APC subset and molecular mechanisms remain unclear. Because dendritic cells (DCs) are the most potent APCs and the NF-kB/Rel family member ReIB is associated with DC maturation and potent APC function, we examined their role in GVHD. Within 4 hours of total body irradiation, ReIB nuclear translocation was increased and restricted to CD11c(hi) DCs within the host APC compartment. Furthermore, the transient depletion of CD11C(hi) donor DCs that reconstitute in the second week after transplantation resulted in a transient decrease in GVHD severity. By using ReIB-/-bone marrow chimeras as transplant recipients or ReIB-/-donor bone marrow, we demonstrate that the induction and maintenance of GVHD is critically dependent on this transcription factor within both host and donor APCs. Critically, ReIB within APCs was required for the expansion of donor helper T cell type 1 (Th1) effectors and subsequent alloreactivity, but not the peripheral expansion or function of donor FoxP3(+) regulatory T cells. These data suggest that the targeted inhibition of nuclear ReIB translocation within APCs represents an attractive therapeutic strategy to dissociate effector and regulatory T-cell function in settings of Th1-mediated tissue injury.