Th2 cell-intrinsic hypo-responsiveness determines susceptibility to helminth infection.
Th2 cell-intrinsic hypo-responsiveness determines susceptibility to helminth infection.
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DOI：
10.1371/journal.ppat.1003215
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发表时间：
2013-03
期刊：
影响因子：
6.7
通讯作者：
Taylor MD
中科院分区：
文献类型：
--
作者：
van der Werf N;Redpath SA;Azuma M;Yagita H;Taylor MD
保护性2型免疫的抑制是驱动蠕虫感染慢性化的主要因素，并且已归因于一系列Th 2细胞外源性免疫调节剂。然而，寄生虫特异性Th 2细胞在慢性免疫下调环境中的内在命运，以及这种命运变化可能对宿主抗性产生的影响尚不清楚。我们使用IL-4gfp报告小鼠证明，在慢性蠕虫感染的丝虫线虫Litomosoides sigmodontis，CD 4 + Th 2细胞的条件朝向一个内在的低反应表型，其特征是功能性的能力，增殖和产生细胞因子IL-4，IL-5和IL-2的损失。Th 2细胞低反应性是决定L. Sigmodontis感染，并且可以通过阻断PD-1在体内逆转，导致Th 2细胞功能质量的长期恢复和增强的抵抗力。与1型环境中的T细胞功能障碍相比，PD-1对Th 2细胞低反应性的控制是通过PD-L2介导的，而不是PD-L1。因此，导致功能低反应表型的Th 2细胞质量的内在变化在确定对丝虫感染的易感性中起关键作用，并且Th 2细胞内在质量的治疗操作为促进对蠕虫的抗性提供了潜在途径。蠕虫寄生虫在全世界超过10亿人中造成慢性感染，其中丝虫线虫感染占1.2亿人。保护性Th 2免疫发展的主要障碍在于感染期间引起的主导下调免疫应答。虽然这种免疫抑制与一系列Th 2细胞-外在免疫调节因子有关，但慢性感染期间CD 4 + Th 2细胞的命运以及Th 2细胞-内在调节在定义对感染的保护性免疫中的作用在很大程度上是未知的。在这项研究中，我们使用的小鼠模型的丝虫感染，以显示，随着感染的进展，Th 2效应细胞负责杀死蠕虫成为功能性低反应，发展表型类似于适应性耐受或衰竭，其清除感染的能力变得受损。我们进一步证明，我们可以通过PD-1/PD-L2共抑制途径治疗性地操纵低反应性Th 2细胞的内在功能质量，以重新唤醒它们并增强对感染的抵抗力。因此，我们的数据提供了第一个证明，Th 2细胞的内在低反应性起着关键作用，在确定蠕虫感染的易感性。
The suppression of protective Type 2 immunity is a principal factor driving the chronicity of helminth infections, and has been attributed to a range of Th2 cell-extrinsic immune-regulators. However, the intrinsic fate of parasite-specific Th2 cells within a chronic immune down-regulatory environment, and the resultant impact such fate changes may have on host resistance is unknown. We used IL-4gfp reporter mice to demonstrate that during chronic helminth infection with the filarial nematode Litomosoides sigmodontis, CD4+ Th2 cells are conditioned towards an intrinsically hypo-responsive phenotype, characterised by a loss of functional ability to proliferate and produce the cytokines IL-4, IL-5 and IL-2. Th2 cell hypo-responsiveness was a key element determining susceptibility to L. sigmodontis infection, and could be reversed in vivo by blockade of PD-1 resulting in long-term recovery of Th2 cell functional quality and enhanced resistance. Contrasting with T cell dysfunction in Type 1 settings, the control of Th2 cell hypo-responsiveness by PD-1 was mediated through PD-L2, and not PD-L1. Thus, intrinsic changes in Th2 cell quality leading to a functionally hypo-responsive phenotype play a key role in determining susceptibility to filarial infection, and the therapeutic manipulation of Th2 cell-intrinsic quality provides a potential avenue for promoting resistance to helminths. Helminth parasites mount chronic infections in over 1 billion people worldwide, of which filarial nematode infections account for 120 million. A major barrier to the development of protective Th2 immunity lies in the dominant down-regulatory immune responses invoked during infection. Although this immune suppression is linked with a range of Th2 cell-extrinsic immune regulators, the fate of CD4+ Th2 cells during chronic infection, and the role of Th2 cell-intrinsic regulation in defining protective immunity to infection is largely unknown. In this study, we use a murine model of filarial nematode infection to show that as infection progresses the Th2 effector cells responsible for killing helminths become functionally hypo-responsive, developing a phenotype similar to adaptive tolerance or exhaustion, and their ability to clear infection becomes impaired. We further demonstrate that we can therapeutically manipulate the intrinsic functional quality of hypo-responsive Th2 cells via the PD-1/PD-L2 co-inhibitory pathway to reawaken them and enhance resistance to infection. Thus, our data provide the first demonstration that Th2 cell-intrinsic hypo-responsiveness plays a key role in determining susceptibility to helminth infection.
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影响因子：
30.5
作者：
Butler, Noah S.;Moebius, Jacqueline;Pewe, Lecia L.;Traore, Boubacar;Doumbo, Ogobara K.;Tygrett, Lorraine T.;Waldschmidt, Thomas J.;Crompton, Peter D.;Harty, John T.
通讯作者：
Harty, John T.
DOI：
10.1084/jem.20101773
发表时间：
2011-05-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fahey LM;Wilson EB;Elsaesser H;Fistonich CD;McGavern DB;Brooks DG
通讯作者：
Brooks DG
影响因子：
15.9
作者：
Borkow, G;Leng, QB;Bentwich, Z
通讯作者：
Bentwich, Z
影响因子：
6.4
作者：
Grogan, JL;Kremsner, PG;Yazdanbakhsh, M
通讯作者：
Yazdanbakhsh, M
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM