T cell-intrinsic regulation, such as anergy, adaptive tolerance and exhaustion, is central to immune regulation. In contrast to Type 1 and Type 17 settings, knowledge of the intrinsic fate and function of Th2 cells in chronic Type 2 immune responses is lacking. We previously showed that Th2 cells develop a PD-1/PD-L2-dependent intrinsically hypo-responsive phenotype during infection with the filarial nematode Litomosoides sigmodontis, denoted by impaired functionality and parasite killing. This study aimed to elucidate the transcriptional changes underlying Th2 cell-intrinsic hypo-responsiveness, and whether it represents a unique and stable state of Th2 cell differentiation. We demonstrated that intrinsically hypo-responsive Th2 cells isolated from L. sigmodontis infected mice stably retained their dysfunctional Th2 phenotype upon transfer to naïve recipients, and had a divergent transcriptional profile to classical Th2 cells isolated prior to hypo-responsiveness and from mice exposed to acute Type 2 stimuli. Hypo-responsive Th2 cells displayed a distinct transcriptional profile to exhausted CD4+ T cells, but upregulated Blimp-1 and the anergy/regulatory-associated transcription factors Egr2 and c-Maf, and shared characteristics with tolerised T cells. Hypo-responsive Th2 cells increased mRNA expression of the soluble regulatory factors Fgl2, Cd38, Spp1, Areg, Metrnl, Lgals3, and Csf1, and a subset developed a T-bet+IFN-γ+ Th2/Th1 hybrid phenotype, indicating that they were not functionally inert. Contrasting with their lost ability to produce Th2 cytokines, hypo-responsive Th2 cells gained IL-21 production and IL-21R blockade enhanced resistance to L. sigmodontis. IL-21R blockade also increased the proportion of CD19+PNA+ germinal centre B cells and serum levels of parasite specific IgG1. This indicates a novel regulatory role for IL-21 during filarial infection, both in controlling protection and B cell responses. Thus, Th2 cell-intrinsic hypo-responsiveness is a distinct and stable state of Th2 cell differentiation associated with a switch from a classically active IL-4+IL-5+ Th2 phenotype, to a non-classical dysfunctional and potentially regulatory IL-21+Egr2+c-Maf+Blimp-1+IL-4loIL-5loT-bet+IFN-γ+ Th2 phenotype. This divergence towards alternate Th2 phenotypes during chronicity has broad implications for the outcomes and treatment of chronic Type 2-related infections and diseases.

中文翻译：

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蠕虫诱导的Th2细胞功能异常与疲劳不同，并且在没有抗原的情况下得以维持。

T细胞内在调节，例如无能，适应性耐受和力竭，对免疫调节至关重要。与1型和17型设置相反，缺乏对Th2细胞在慢性2型免疫应答中的固有命运和功能的了解。我们以前表明Th2细胞在感染丝状线虫Litomosoides sigmodontis的过程中会发展出PD-1 / PD-L2依赖性的内在低反应性表型，以功能受损和寄生虫杀伤为特征。这项研究旨在阐明潜在的Th2细胞内在反应低下的转录变化，以及它是否代表Th2细胞分化的独特而稳定的状态。我们证明了从L中分离出的本质上反应低下的Th2细胞。感染sigmodontis的小鼠在转移到初次接受者后会稳定地保留其功能失调的Th2表型，并且对低反应性之前和暴露于急性2型刺激的小鼠中分离的经典Th2细胞具有不同的转录谱。低反应性Th2细胞显示出与疲惫的CD4 + T细胞截然不同的转录谱，但上调了Blimp-1和与无反应/调节相关的转录因子Egr2和c-Maf，并与耐受的T细胞共有特征。低反应性Th2细胞增加了可溶性调节因子Fgl2，Cd38，Spp1，Areg，Metrnl，Lgals3和Csf1的mRNA表达，并且有一个子集形成了T-bet +IFN-γ+ Th2 / Th1杂合表型，表明它们在功能上不是惰性的。与他们丧失产生Th2细胞因子的能力相反，低反应性Th2细胞获得IL-21的产生，IL-21R的阻断增强了对Sigmodontis的抵抗力。IL-21R阻断剂还增加了CD19 + PNA +生发中心B细胞的比例和寄生虫特异性IgG1的血清水平。这表明在丝状感染期间，IL-21在控制保护和B细胞反应中均具有新的调节作用。因此，Th2细胞固有的低反应性是Th2细胞分化的一种独特而稳定的状态，与经典活动的IL-4 + IL-5 + Th2表型向非经典功能障碍且可能具有调节作用的IL-21的转换有关。 + Egr2 + c-Maf + Blimp-1 + IL-4loIL-5loT-bet +IFN-γ+ Th2表型。慢性期间这种向其他Th2表型的分化对慢性2型相关感染和疾病的结果和治疗具有广泛的意义。