Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis
Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis
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DOI：
10.1016/j.celrep.2017.03.007
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发表时间：
2017-03-28
期刊：
影响因子：
8.8
通讯作者：
Barber, Daniel L.
中科院分区：
文献类型：
--
作者：
Sallin, Michelle A.;Sakai, Shunsuke;Barber, Daniel L.
最近的数据表明，Th 1细胞的分化状态决定了它们对结核病的保护能力。因此，我们研究了Th 1极化因子在产生结核分枝杆菌特异性Th 1细胞的保护性和非保护性亚群中的作用。我们发现IL-12/23 p40促进Th 1细胞扩增和成熟超过CD 73（+）CXCR 3（+）T-bet（dim）阶段，并且T-bet防止Th 1细胞偏离为Th 17细胞。然而，IL-12/23 p40和T-bet对于产生血管内CX 3CR 1（+）KLRG 1（+）Th 1细胞的显著亚群也是必不可少的，这些细胞持续性差，既不能迁移到肺实质中，也不能控制结核分枝杆菌生长。此外，T-bet抑制肺中CD 69（+）CD 103（+）组织驻留表型效应物的发展。相反，Th 1细胞衍生的IFN-γ抑制血管内CX 3CR 1（+）KLRG 1（+）Th 1细胞的积聚。因此，虽然IL-12和T-bet是必需的宿主存活因子，但它们同时在几个水平上对抗肺CD 4 T细胞应答，证明了结核病中Th 1极化的双重性质。
Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73(+)CXCR3(+)T-bet(dim) stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL-12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1(+)KLRG1(+) Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69(+)CD103(+) tissue resident phenotype effectors in lung. In contrast, Th1-cell-derived IFN-gamma inhibits the accumulation of intravascular CX3CR1(+)KLRG1(+) Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis.