A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis.
A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis.
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DOI：
10.1371/journal.ppat.1002375
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发表时间：
2011-11
期刊：
影响因子：
6.7
通讯作者：
Kaminski WE
中科院分区：
文献类型：
--
作者：
Beham AW;Puellmann K;Laird R;Fuchs T;Streich R;Breysach C;Raddatz D;Oniga S;Peccerella T;Findeisen P;Kzhyshkowska J;Gratchev A;Schweyer S;Saunders B;Wessels JT;Möbius W;Keane J;Becker H;Ganser A;Neumaier M;Kaminski WE
巨噬细胞在宿主防御分枝杆菌感染中起核心作用，抗TNF治疗与人类肉芽肿组织解体和结核病再活化有关。在这里，我们提供了在人和小鼠单核细胞和巨噬细胞亚群中存在基于T细胞受体（TCR）αβ的重组免疫受体的证据。在体外，我们发现巨噬细胞-TCR αβ诱导CCL 2的释放并调节吞噬作用。TNF阻断抑制巨噬细胞-TCR αβ表达。来自健康个体的巨噬细胞感染分枝杆菌触发表达限制性TCR Vβ库的簇的形成。在体内，携带TCRαβ的巨噬细胞大量聚集在肺结核患者干酪样肉芽肿的宿主-病原体接触区。在嵌合小鼠模型中，即使在存在完整T细胞的情况下，可变巨噬细胞-TCR αβ或TNF的缺失也与肺结核的结构受损肉芽肿相关。这些结果揭示了单核细胞/巨噬细胞中TNF调节的重组免疫受体，并证明其在结核病肉芽肿形成中的意义。分枝杆菌感染导致宿主反应，这导致肉芽肿的形成，肉芽肿是以巨噬细胞的存在为特征的高度组织化的结构，巨噬细胞被认为仅依赖于不变的免疫受体。另一方面，肉芽肿形成需要可变免疫受体的存在，但该过程不仅仅依赖于T细胞。此外，TNF是维持人类分枝杆菌肉芽肿结构所必需的。我们现在发现了人类和小鼠巨噬细胞亚群表达可变αβ T细胞受体（TCRαβ）的证据。巨噬细胞-TCR αβ的接合触发CCL 2释放，并且针对该受体的诱饵的吞噬作用增强。携带TCRαβ的巨噬细胞在人结核肉芽肿中积累，并且巨噬细胞的抗TNF治疗导致TCRαβ的下调，这与半胱天冬酶3切割和TCR α β的抑制有关。抗TNF治疗减少分枝杆菌诱导的TCRαβ阳性巨噬细胞簇形成，这与rag 1-/-（T细胞rag 1 +/+）和TNF-/-（T细胞TNF+/+）嵌合小鼠中肉芽肿形成减少一致。因此，两种嵌合体在分枝杆菌感染后显示出减少的CCL 2染色。总之，我们已经确定了单核细胞/巨噬细胞中的重组免疫受体，并证明其在分枝杆菌感染中的意义。
Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αβ based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαβ induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage-TCRαβ expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR Vβ repertoires. In vivo, TCRαβ bearing macrophages abundantly accumulate at the inner host-pathogen contact zone of caseous granulomas from patients with lung tuberculosis. In chimeric mouse models, deletion of the variable macrophage-TCRαβ or TNF is associated with structurally compromised granulomas of pulmonary tuberculosis even in the presence of intact T cells. These results uncover a TNF-regulated recombinatorial immune receptor in monocytes/macrophages and demonstrate its implication in granuloma formation in tuberculosis. Infection with mycobacteria results in a host response which results in the formation of granulomas, highly organized structures characterized by the presence of macrophages, which are considered to rely solely on invariant immune receptors. On the other hand, the presence of variable immune receptors is required for granuloma formation but this process is not solely dependent on T cells. Furthermore, TNF is required for the maintenance of the mycobacterial granuloma structure in humans. We now find evidence for subpopulations of human and mouse macrophages that express variable αβ T cell receptors (TCRαβ). Engagement of the macrophage-TCRαβ triggers CCL2 release and phagocytosis of baits directed to this receptor is enhanced. TCRαβ bearing macrophages accumulate in human tuberculosis granulomas and anti-TNF treatment of macrophages results in downregulation of the TCRαβ, which is associated with caspase 3 cleavage and suppression of TCRξ. Anti-TNF treatment reduces mycobacteria induced cluster formation of TCRαβ positive macrophages, which is in line with reduced granuloma formation in rag1–/–(T cell rag1+/+) and TNF–/–(T cell TNF+/+) chimeric mice. Consequently, both chimeras show reduced CCL2 staining after mycobacterial infection. In summary, we have identified a recombinatorial immunoreceptor in monocytes/macrophages and demonstrate its implication in mycobacterial infection.
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