Lutshumba Jenny, Ochiai Eri, Sa Qila, Anand Namrata, Suzuki Yasuhiro
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, Kentucky, USA
mSystems. 2020 Apr 14;5(2):e00189-20. doi: 10.1128/mSystems.00189-20.
We recently found that an invasion of CD8 cytotoxic T cells into tissue cysts of initiates an elimination of the cysts in association with an accumulation of microglia and macrophages. In the present study, we compared mRNA levels for 734 immune-related genes in the brains of infected SCID mice that received perforin-sufficient or -deficient CD8 immune T cells at 3 weeks after infection. At 7 days after the T cell transfer, mRNA levels for only six genes were identified to be greater in the recipients of the perforin-sufficient T cells than in the recipients of the perforin-deficient T cells. These six molecules included two T cell costimulatory molecules, inducible T cell costimulator receptor (ICOS) and its ligand (ICOSL); two chemokine receptors, C-X-C motif chemokine receptor 3 (CXCR3) and CXCR6; and two molecules related to an activation of microglia and macrophages, interleukin 18 receptor 1 (IL-18R1) and chitinase-like 3 (Chil3). Consistently, a marked reduction of cyst numbers and upregulation of ICOS, CXCR3, CXCR6, IL-18R1, and Chil3 mRNA levels were also detected when the perforin-sufficient CD8 immune T cells were transferred to infected SCID mice at 6 weeks after infection, indicating that the CD8 T cell-mediated protective immunity is capable of eliminating mature cysts. These results together suggest that ICOS-ICOSL interactions are crucial for activating CD8 cytotoxic immune T cells to initiate the destruction of cysts and that CXCR3, CXCR6, and IL-18R are involved in recruitment and activation of microglia and macrophages to the T cell-attacked cysts for their elimination. establishes a chronic infection by forming tissue cysts, which can grow into sizes greater than 50 μm in diameter as a consequence of containing hundreds to thousands of organisms surrounded by the cyst wall within infected cells. Our recent studies using murine models uncovered that CD8 cytotoxic T cells penetrate into the cysts in a perforin-dependent manner and induce their elimination, which is accompanied with an accumulation of phagocytic cells to the T cell-attacked target. This is the first evidence of the ability of the T cells to invade into a large target for its elimination. However, the mechanisms involved in anticyst immunity remain unclear. Immune profiling analyses of 734 immune-related genes in the present study provided a valuable foundation to initiate elucidating detailed molecular mechanisms of the novel effector function of the immune system operated by perforin-mediated invasion of CD8 T cells into large targets for their elimination.
我们最近发现，CD8细胞毒性T细胞侵入组织囊肿会引发囊肿的清除，同时伴有小胶质细胞和巨噬细胞的聚集。在本研究中，我们比较了感染后3周接受穿孔素充足或缺乏的CD8免疫T细胞的感染SCID小鼠大脑中734个免疫相关基因的mRNA水平。在T细胞转移后7天，仅发现6个基因的mRNA水平在接受穿孔素充足T细胞的受体中高于接受穿孔素缺乏T细胞的受体。这6种分子包括两种T细胞共刺激分子，诱导性T细胞共刺激受体（ICOS）及其配体（ICOSL）；两种趋化因子受体，C-X-C基序趋化因子受体3（CXCR3）和CXCR6；以及两种与小胶质细胞和巨噬细胞激活相关的分子，白细胞介素18受体1（IL-18R1）和几丁质酶样3（Chil3）。同样，当在感染后6周将穿孔素充足的CD8免疫T细胞转移到感染的SCID小鼠时，也检测到囊肿数量显著减少以及ICOS、CXCR3、CXCR6、IL-18R1和Chil3 mRNA水平上调，表明CD8 T细胞介导的保护性免疫能够消除成熟的囊肿。这些结果共同表明，ICOS-ICOSL相互作用对于激活CD8细胞毒性免疫T细胞以启动囊肿破坏至关重要，并且CXCR3、CXCR6和IL-18R参与将小胶质细胞和巨噬细胞募集并激活到T细胞攻击的囊肿处以进行清除。通过形成组织囊肿建立慢性感染，由于感染细胞内的囊肿壁包围着数百到数千个生物体，囊肿可生长到直径大于50μm。我们最近使用小鼠模型的研究发现，CD8细胞毒性T细胞以穿孔素依赖的方式穿透囊肿并诱导其清除，这伴随着吞噬细胞向T细胞攻击的靶标聚集。这是T细胞侵入大靶标以进行清除能力的首个证据。然而，抗囊肿免疫所涉及的机制仍不清楚。本研究中对734个免疫相关基因的免疫谱分析为开始阐明由穿孔素介导的CD8 T细胞侵入大靶标以进行清除所操作的免疫系统新效应功能详细分子机制提供了有价值的基础。
