PDF(Pubmed)
Abstract：
Acute systemic inflammation critically alters the function of the immune system, often promoting myelopoiesis at the expense of lymphopoiesis. In the thymus, systemic inflammation results in acute thymic atrophy and, consequently, impaired T-lymphopoiesis. The mechanism by which systemic inflammation impacts the thymus beyond suppressing T-cell development is still unclear. Here, we describe how the synergism between TL1A and IL-18 suppresses T-lymphopoiesis to promote thymic myelopoiesis. The protein levels of these two cytokines were elevated in the thymus during viral-induced thymus atrophy infection with murine cytomegalovirus (MCMV) or pneumonia virus of mice (PVM). In vivo administration of TL1A and IL-18 induced acute thymic atrophy, while thymic neutrophils expanded. Fate mapping with Ms4a3-Cre mice demonstrated that thymic neutrophils emerge from thymic granulocyte-monocyte progenitors (GMPs), while Rag1-Cre fate mapping revealed a common developmental path with lymphocytes. These effects could be modeled ex vivo using neonatal thymic organ cultures (NTOCs), where TL1A and IL-18 synergistically enhanced neutrophil production and egress. NOTCH blockade by the LY411575 inhibitor increased the number of neutrophils in the culture, indicating that NOTCH restricted steady-state thymic granulopoiesis. To promote myelopoiesis, TL1A, and IL-18 synergistically increased GM-CSF levels in the NTOC, which was mainly produced by thymic ILC1s. In support, TL1A- and IL-18-induced granulopoiesis was completely prevented in NTOCs derived from Csf2rb-/- mice and by GM-CSFR antibody blockade, revealing that GM-CSF is the essential factor driving thymic granulopoiesis. Taken together, our findings reveal that TL1A and IL-18 synergism induce acute thymus atrophy while promoting extramedullary thymic granulopoiesis in a NOTCH and GM-CSF-controlled manner.
摘要：
急性全身炎症严重改变免疫系统的功能，通常以淋巴细胞生成为代价促进骨髓生成。在胸腺里,全身性炎症导致急性胸腺萎缩，因此,T淋巴细胞生成受损。全身性炎症影响胸腺而不是抑制T细胞发育的机制尚不清楚。这里,我们描述了TL1A和IL-18之间的协同作用如何抑制T淋巴细胞生成以促进胸腺骨髓生成。在病毒诱导的小鼠巨细胞病毒（MCMV）或小鼠肺炎病毒（PVM）感染胸腺萎缩期间，胸腺中这两种细胞因子的蛋白质水平升高。体内施用TL1A和IL-18诱导的急性胸腺萎缩，而胸腺中性粒细胞扩张。Ms4a3-Cre小鼠的命运作图表明，胸腺中性粒细胞从胸腺粒细胞-单核细胞祖细胞（GMPs）中出现，而Rag1-Cre命运图谱揭示了淋巴细胞的共同发育路径。这些影响可以使用新生儿胸腺器官培养物(NTOC)进行离体建模，其中TL1A和IL-18协同增强中性粒细胞的产生和流出。LY411575抑制剂阻断NOTCH增加了培养物中嗜中性粒细胞的数量，表明NOTCH限制了胸腺的稳态粒细胞生成。为了促进骨髓生成，TL1A,和IL-18协同增加NTOC中的GM-CSF水平，主要由胸腺ILC1s产生。支持,在来自Csf2rb-/-小鼠的NTOC中，TL1A-和IL-18诱导的粒细胞生成被完全阻止，并且通过GM-CSFR抗体阻断，揭示GM-CSF是驱动胸腺粒细胞生成的重要因素。一起来看,我们的研究结果表明,TL1A和IL-18协同作用诱导急性胸腺萎缩,同时以NOTCH和GM-CSF控制的方式促进髓外胸腺粒细胞生成.
