The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin β receptor signaling to achieve homeostasis of dendritic cells
The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin β receptor signaling to achieve homeostasis of dendritic cells
复制标题
DOI：
10.4049/jimmunol.180.1.238
复制
发表时间：
2008-01-01
影响因子：
4.4
通讯作者：
Ware, Carl F.
中科院分区：
文献类型：
--
作者：
De Trez, Carl;Schneider, Kirsten;Ware, Carl F.
脾脏中树突状细胞（DC）的增殖受正性生长信号的调节，这些信号是通过光敏素（LT）-β受体实现的;然而，实现稳态控制的对抗抑制信号尚未得到解决。LT α、LT β、LT β R和NF κ B诱导激酶缺陷的小鼠表现出CD 8（-）DC亚群的特异性丧失。相反，在疱疹病毒进入介体（HVEM）或B和T淋巴细胞衰减因子（BTLA）缺陷的小鼠中，CD 8 α（-）DC亚群过度增殖。HVEM和BTLA缺陷的DC亚群在竞争性置换骨髓嵌合小鼠中重建脾脏时显示出特异性生长优势。DC和周围微环境中需要HVEM和BTLA的表达，尽管DC表达LT β R是维持稳态所必需的。此外，用激动剂Ab强制激活LT β R驱动了CD 8 α（-）DC亚群的扩增，压倒了HVEM-BTLA途径的调节。这些结果表明HVEM-BTLA通路为淋巴组织中的DC稳态提供了抑制性检查点。LT β R和HVEM-BTLA通路共同形成调节DC稳态的整合信号传导网络。
Proliferation of dendritic cells (DC) in the spleen is regulated by positive growth signals through the lymphotoxin (LT)-beta receptor; however, the countering inhibitory signals that achieve homeostatic control are unresolved. Mice deficient in LT alpha, LT beta;, LT beta R, and the NF kappa B inducing kinase show a specific loss of CD8(-) DC subsets. In contrast, the CD8 alpha(-) DC subsets were overpopulated in mice deficient in the herpesvirus entry mediator (HVEM) or B and T lymphocyte attenuator (BTLA). HVEM- and BTLA-deficient DC subsets displayed a specific growth advantage in repopulating the spleen in competitive replacement bone marrow chimeric mice. Expression of HVEM and BTLA were required in DC and in the surrounding microenvironment, although DC expression of LT beta R was necessary to maintain homeostasis. Moreover, enforced activation of the LT beta R with an agonist Ab drove expansion of CD8 alpha(-) DC subsets, overriding regulation by the HVEM-BTLA pathway. These results indicate the HVEM-BTLA pathway provides an inhibitory checkpoint for DC homeostasis in lymphoid tissue. Together, the LT beta R and HVEM-BTLA pathways form an integrated signaling network regulating DC homeostasis.