Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection-猫眼课题宝

DOI：

10.1096/fj.09-138057

发表时间：

2009-11-01

期刊：

FASEB JOURNAL

影响因子：

4.8

通讯作者：

中科院分区：

生物学2区

文献类型：

作者：

Barbi, Joseph;Snider, Heidi M.;Satoskar, Abhay R.

信号转导和转录激活因子1(STAT1)信号通路介导了干扰素-γ的生物学功能。我们先前已经证明，STAT1通路对于宿主抵抗主要利什曼原虫感染是不可或缺的。在这项研究中，我们通过将野生型(WT)和STAT1(-/-)C57BL/6小鼠的T细胞转移到Rag2(-/-)C57BL/6小鼠中，研究了淋巴细胞中的STAT1，特别是CD4(+)和CD8(+)T细胞在介导抗梅毒小鼠免疫中的作用。由未分离的STAT1(-/-)脾细胞(B细胞和T细胞)重组的RAG2(-/-)小鼠在感染主要乳杆菌后不能产生有效的Th1反应，产生更多的IL-4，并出现充满寄生虫的大病变。相反，用WT(STAT1(+/+))脾细胞重组的Rag2(-/-)小鼠启动Th1反应并发展成自我解决的病变。使用接受来自WT或STAT1(-/-)小鼠的纯化的CD4(+)和CD8(+)T细胞组合的Rag2(-/-)受者的研究表明，在感染主要乳杆菌后，CD4(+)T细胞中的STAT1缺乏，而CD8(+)T细胞中的STAT1缺乏，导致慢性、不可愈合的病变的发展和寄生虫的系统性传播。使用WT Thy1.1(+)和STAT1(-/-)Thy1.2(+)T细胞的Rag2(-/-)受体的进一步研究表明，在主要乳杆菌感染期间，CD4(+)T细胞中的STAT1不是Th1分化所必需的。然而，CXCR3对CD4(+)T细胞的上调及其向区域淋巴结和皮肤感染部位的迁移是至关重要的。综上所述，这些研究表明，CD4(+)T细胞中的STAT1通路通过控制Th1细胞向感染部位的迁移而不是它们的产生，在抗L.main的免疫中发挥关键作用。此外，他们还揭示了CD4(+)T细胞STAT1在防止主要利什曼原虫感染的系统性传播中的重要作用。-Barbi，J.，Snider，H.M.，Bhardwaj，N.，Lezama-Davila，C.M.，Durbin，J.E.，Satoskar，A.R.信号转导和转录激活因子1在对主要利什曼原虫的免疫中发挥着不可或缺的作用，它通过调节Th1细胞归巢到感染部位。FASE B J.23,3990-3999(2009)。Www.fasebj.org

The signal transducer and activator of transcription 1 (STAT1) signaling pathway mediates the biological functions of IFN-gamma. We have previously shown that the STAT1 pathway is indispensable for host resistance against Leishmania major infection. In this study, we examined the role of STAT1 in lymphocytes and specifically CD4(+) and CD8(+) T cells in mediating immunity against L. major by transferring T cells from wild-type (WT) and STAT1(-/-) C57BL/6 mice into Rag2(-/-) C57BL/6 mice. Rag2(-/-) mice reconstituted with unfractionated STAT1(-/-) splenocytes (B cells and T cells) failed to mount an efficient Th1 response after L. major infection, produced more IL-4, and developed large lesions full of parasites. In contrast, Rag2(-/-) mice reconstituted with WT (STAT1(+/+)) splenocytes mounted a Th1 response and developed self-resolving lesions. Studies using Rag2(-/-) recipients that received a combination of purified CD4(+) and CD8(+) T cells from WT or STAT1(-/-) mice revealed that STAT1 deficiency in CD4(+) T cells, but not in CD8(+) T cells, leads to development of chronic, nonhealing lesions and systemic dissemination of parasites into the spleen after L. major infection. Further studies using Rag2(-/-) recipients of WT Thy1.1(+) and STAT1(-/-) Thy1.2(+) T cells showed that STAT1 in CD4(+) T cells was not required for Th1 differentiation during L. major infection. However, it was critical for up-regulation of CXCR3 on CD4(+) T cells and their migration to the regional lymph node and the cutaneous site of infection. Together, these studies indicate that the STAT1 pathway in CD4(+) T cells plays a critical role in immunity against L. major by controlling the migration of Th1 cells to the site of infection rather than their generation. Further, they reveal an essential role for CD4(+) T cell STAT1 in preventing systemic dissemination of L. major infection.-Barbi, J., Snider, H. M., Bhardwaj, N., Lezama-Davila, C. M., Durbin, J. E., Satoskar, A. R. Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection. FASEB J. 23, 3990-3999 (2009). www.fasebj.org

Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection

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