Maternal schistosomiasis impairs offspring Interleukin-4 production and B cell expansion.
Maternal schistosomiasis impairs offspring Interleukin-4 production and B cell expansion.
复制标题
母亲血吸虫病损害后代白细胞介素-4的产生和B细胞扩增。
DOI：
10.1371/journal.ppat.1009260
复制
发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Fairfax KC
中科院分区：
文献类型：
--
作者：
Cortés-Selva D;Gibbs L;Ready A;Ekiz HA;O'Connell R;Rajwa B;Fairfax KC
流行病学研究已确定母体蠕虫感染与对某些幼儿疫苗免疫力降低之间存在相关性，但对此的细胞基础了解甚少。在此，我们利用母体血吸虫病的双白细胞介素 - 4（IL - 4）报告小鼠模型，研究了母体曼氏血吸虫感染对后代稳态免疫以及商业破伤风/白喉疫苗诱导的免疫的影响。我们证明，曼氏血吸虫感染的母体所生育的后代在稳态时循环浆细胞和外周淋巴结滤泡树突状细胞减少。这些减少与不变自然杀伤T细胞（iNKT细胞）产生的IL - 4减少相关，iNKT细胞是生命早期外周淋巴结中IL - 4的细胞来源。滤泡树突状细胞和IL - 4产生的这些缺陷长期存在，表现为生发中心IL - 4分泌减少以及破伤风/白喉疫苗免疫后辅助性T细胞（TFH）、记忆B细胞和记忆T细胞生成减少。在对后代进行破伤风/白喉疫苗免疫后，利用单细胞RNA测序，我们发现除了大多数滤泡B细胞中关键的B细胞转录因子Ebf - 1减少外，细胞周期和细胞增殖途径也存在缺陷。这些减少取决于母体中是否存在虫卵抗原，因为单一性别感染的母体所生育的后代没有这些转录缺陷。这些数据表明，母体血吸虫病导致抗原诱导的细胞免疫长期存在缺陷，并首次为调节曼氏血吸虫感染的母体所生育后代免疫力降低的因素提供了关键的机制性见解。
母体蠕虫感染是全球公共卫生关注的问题，与婴儿对某些儿童免疫接种的免疫反应改变相关，但对于母体蠕虫感染如何改变后代细胞免疫反应缺乏机制上的了解。在此我们在双IL - 4报告小鼠中建立了母体曼氏血吸虫感染的模型。我们发现，曼氏血吸虫感染的母体所生育的后代在体内平衡期间以及破伤风 - 白喉疫苗免疫后IL - 4产生受损。我们确定iNKT细胞是生命早期体内平衡期间IL - 4的主要来源，并且IL - 4产生减少与B细胞和滤泡树突状细胞反应降低均相关。这些缺陷长期存在，影响记忆B细胞和T细胞反应。对免疫后的后代进行单细胞RNA测序分析，确定了B细胞细胞周期和增殖相关基因的减少依赖于虫卵抗原。这些数据揭示母体感染导致对异源抗原的细胞反应长期存在缺陷，并为母体感染对后代免疫力的影响提供了重要见解。
Epidemiological studies have identified a correlation between maternal helminth infections and reduced immunity to some early childhood vaccinations, but the cellular basis for this is poorly understood. Here, we investigated the effects of maternal Schistosoma mansoni infection on steady-state offspring immunity, as well as immunity induced by a commercial tetanus/diphtheria vaccine using a dual IL-4 reporter mouse model of maternal schistosomiasis. We demonstrate that offspring born to S. mansoni infected mothers have reduced circulating plasma cells and peripheral lymph node follicular dendritic cells at steady state. These reductions correlate with reduced production of IL-4 by iNKT cells, the cellular source of IL-4 in the peripheral lymph node during early life. These defects in follicular dendritic cells and IL-4 production were maintained long-term with reduced secretion of IL-4 in the germinal center and reduced generation of TFH, memory B, and memory T cells in response to immunization with tetanus/diphtheria. Using single-cell RNASeq following tetanus/diphtheria immunization of offspring, we identified a defect in cell-cycle and cell-proliferation pathways in addition to a reduction in Ebf-1, a key B-cell transcription factor, in the majority of follicular B cells. These reductions are dependent on the presence of egg antigens in the mother, as offspring born to single-sex infected mothers do not have these transcriptional defects. These data indicate that maternal schistosomiasis leads to long-term defects in antigen-induced cellular immunity, and for the first time provide key mechanistic insight into the factors regulating reduced immunity in offspring born to S. mansoni infected mothers. Maternal helminth infections are a global public health concern and correlate with altered infant immune responses to some childhood immunizations, but a mechanistic understanding of how maternal helminth infection alters the cellular immune responses of offspring is lacking. Here we establish a model of maternal Schistosoma mansoni infection in dual IL-4 reporter mice. We find that offspring born to mothers infected with S. mansoni have impaired production of IL-4 during homeostasis, and following immunization with a Tetanus-Diphtheria vaccine. We identified that iNKT cells are the dominant source of IL-4 during early life homeostasis, and that diminished IL-4 production was associated with both reduced B cell and follicular dendritic cell responses. These defects were maintained long-term, affecting memory B and T cell responses. Single-cell RNASeq analysis of immunized offspring identified egg antigen-dependent reductions in B-cell cell cycle and proliferation-related genes. These data reveal that maternal infection leads to long-lasting defects in the cellular responses to heterologous antigens and provide vital insight into the influence of maternal infection on offspring immunity.
登录
查看更多内容
DOI：
10.4049/jimmunol.1401225
发表时间：
2015-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fairfax KC;Everts B;Amiel E;Smith AM;Schramm G;Haas H;Randolph GJ;Taylor JJ;Pearce EJ
通讯作者：
Pearce EJ
影响因子：
3
作者：
Ekiz, H. Atakan;Conley, Christopher J.;O'Connell, Ryan M.
通讯作者：
O'Connell, Ryan M.
影响因子：
3.5
作者：
FIRBANK, M;HIRAOKA, M;DELPY, DT
通讯作者：
DELPY, DT
影响因子：
4.4
作者：
Hara, Takahiro;Shitara, Soichiro;Ikuta, Koichi
通讯作者：
Ikuta, Koichi
影响因子：
3.1
作者：
DESOWITZ, RS;ELM, J;ALPERS, MP
通讯作者：
ALPERS, MP