Interleukin-3 producing IRA B cells as mediators of acute and delayed immune responses during inflammation

免疫系统由先天和适应性成分组成，它们密切相关，保护宿主免受感染。在感染期间，由于免疫反应过度或减弱，宿主可能处于危险之中。因此，一个主要的治疗目标是在控制感染和控制炎症之间建立平衡。一个有希望的策略是利用内源性免疫系统来增强有益的过程，抑制有害的过程。然而，这样的策略需要对疾病的病理生理有深入的、机械的理解。最近，我们发现了一种名为先天反应激活因子（IRA） B细胞的新细胞。腹腔感染通过TLR4/MyD88信号激活先天类B1a B细胞。因此，活化的B1a B细胞迁移出腹膜，在淋巴器官中积累，并分化为粒细胞/巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-3 （IL-3）产生的IRA B细胞。IRA B细胞在急性炎症中产生GM-CSF的功能最近被研究。然而，造血细胞因子IL-3在急性/先天和延迟/适应性免疫反应中的作用仍处于初级阶段。我们假设IRA B细胞通过产生IL-3，通过促进单核细胞、中性粒细胞和浆细胞样树突状细胞（pDCs）的产生，是急性和延迟免疫反应的主要调节剂。我们的假设是基于一些自己发表的和未发表的数据：(i) IRA B细胞是急性炎症小鼠模型中IL-3的主要来源，与对照组相比，IL-3敲除小鼠（ii）不会屈服于败血症，这是一种众所周知的急性炎症模型；（iii）急性炎症不产生ly - 6high单核细胞；（iv）不产生il -1 β、IL-6和TNFalpha；(v)在继发性肺部感染模型中不能产生pDCs。我们将使用基因敲除动物模型、复杂的外科技术以及经典的分子和细胞生物学工具来验证这一假设。该项目很重要，因为它基于一个强大的表型，具有明确的转化潜力：IL-3可能被认为是治疗急性炎症和败血症的治疗靶点。该项目具有创新性，因为它探索了一种新发现细胞的生物学特性，并将确定IL-3在急性/先天和延迟/适应性免疫反应中的新功能。

The immune system consists of innate and adaptive components that operate in close proximity to protect the host against infections. During infection the host can be at risk due to overwhelming or diminished immune responses. A major therapeutic goal, then, is to establish a balance between controlling infection and controlling inflammation. One promising strategy is to harness the endogenous immune system to augment processes that are beneficial and curb processes that cause harm. Such strategies, however, require an in-depth, mechanistic understanding of the diseases pathophysiology. Recently, we discovered a new cell named the innate response activator (IRA) B cell. Infection of the peritoneal cavity activates innate like B1a B cells via TLR4/MyD88 signalling. As a consequence, activated B1a B cells migrate out of the peritoneum, accumulate in lymphoid organs, and differentiate to granulocyte/macrophages-colony stimulating factor (GM-CSF) and interleukin-3 (IL-3) producing IRA B cells.The function of IRA B cell produced GM-CSF during acute inflammation has been investigated recently. However, the role of the hematopoietic cytokine IL-3 in acute/innate and delayed/adaptive immune responses is still rudimentary understood. We hypothesise that IRA B cells - via the production of IL-3 -are master regulators of acute and delayed immune responses by promoting the generation of monocytes, neutrophils and plasmacytoid dendritic cells (pDCs). Our hypothesis is based on several own published and unpublished data: (i) IRA B cells are a major source of IL-3 in a mouse model of acute inflammation and compared to controls, IL-3 knockout mice (ii) do not succumb to sepsis, a well known model for acute inflammation; (iii) do not produce Ly-6Chigh monocytes in acute inflammation; (iv) do not produce IL-1beta, IL-6, and TNFalpha; and (v) fail to produce pDCs in a model of secondary pulmonary infection.We will test the hypothesis using gene-knockout animal models, sophisticated surgical techniques, and classical molecular and cell biology tools. The project is important because it is based on a strong phenotype and has clear translational potential: IL-3 may be considered as a therapeutic target for the treatment of acute inflammation and sepsis. The project is innovative because it explores the biology of a newly-discovered cell and will identify new functions for IL-3 in both, acute/innate and delayed/adaptive immune responses.