Cutler Antony J, Oliveira Joao, Ferreira Ricardo C, Challis Ben, Walker Neil M, Caddy Sarah, Lu Jia, Stevens Helen E, Smyth Deborah J, Pekalski Marcin L, Kennet Jane, Hunter Kara M D, Goodfellow Ian, Wicker Linda S, Todd John A, Waldron-Lynch Frank
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Center for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK.
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus,Cambridge, CB2 0XY, UK.
Wellcome Open Res. 2017 Oct 5;2:28. doi: 10.12688/wellcomeopenres.11300.3. eCollection 2017.
The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen.
Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel.
Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4 T cell (Treg), effector T cell (Teff) CD4 and CD8 subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later. NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69 and Ki-67 effector memory Teffs were followed by the emergence of memory CD8 Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues.
The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection.
在1型糖尿病白细胞介素-2剂量对调节性T细胞的适应性研究（DILT1D）中，一名参与者感染了诺如病毒，这使得我们能够详细了解针对这种常见胃肠道病原体的细胞和细胞因子免疫反应。
在感染发生前和发生后，采集系列血液、血清和外周血单个核细胞（PBMC）样本。为了区分对诺如病毒的免疫反应以及单独使用单剂量阿地白介素（重组白细胞介素-2，rIL-2）的对照情况，对五名接受相似剂量的未感染参与者的样本进行了平行分析。
诺如病毒感染为自限性，在24小时内消退，随后产生抗诺如病毒抗体。血清促炎和抗炎细胞因子水平，包括IL-10，在感染的症状期达到峰值，同时单核细胞和中性粒细胞频率增加。与此同时，调节性CD4 T细胞（Treg）、效应T细胞（Teff）CD4和CD8亚群的频率动态降低，在24小时后的下一个采样点反弹至基线水平或更高。NK细胞和NKT细胞短暂增加CD69表达，经典单核细胞表达增加水平的CD40、HLA-DR和SIGLEC-1，这些都是干扰素反应的生物标志物。我们还观察到Teffs的激活和动员，其中CD69和Ki-67效应记忆Teffs频率增加，随后出现表达黏膜组织归巢标志物CD103和β7整合素的记忆CD8 Teff。Treg反应与先天细胞、Teff和细胞因子反应一致。感染后关键的Treg分子FOXP3、CTLA-4和CD25上调，同时能够归巢到组织的Treg频率增加。
结果说明了对诺如病毒感染的先天、适应性和反调节免疫反应。低剂量IL-2给药诱导了感染期间观察到的许多Treg反应。
