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

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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 Our hypothesis is based on several own published and unpublished data: (i) IRA B cells are a major source of IL-3 in a mouse model of acute inflammation and compared to controls, IL-3 knockout mice (ii) do not succumb to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.