Airway inflammation induced by various allergens, pollution, and infections is a major underlying cause of asthma, a disease with alarming increases in incidence and mortality in the western countries in the past two decades. We seek to understand the cellular and molecular basis for exacerbation of asthma. Our immediate goal is to investigate the mechanisms by which CD4+ T helper cells (Th) regulate differentiation of innate Th2-type effector cells. Both CD4+ Th 2 cells and Th2-type innate effector cells have been shown to play critical roles in causing allergic airway inflammation by producing interleukin (IL)-4, IL-5, IL-9, IL-13 and IL-25. However, the mechanisms by which CD4+ Th2 cells regulate innate Th2-type effector cells are unknown. We studied these mechanisms by using IL-4 reporter mice. We found that IL-4 plays an important role in the differentiation of Th2 cytokine-producing innate cells both in vivo and in vitro. Based on our preliminary findings, we hypothesize that IL-4 primes bone marrow progenitor cells into Th2-type innate effector cells via a GATAS-dependent mechanism, while IL-5 does so via TAT5/GATA1-dependent mechanisms. We propose three specific aims to test our hypothesis.
in Aim 1, we will determine whether CD4+Th2 effector cells coordinate with innate cells to generate Th2-type immunity through secretion of IL-4 and IL-5.
In Aim 2, we will determine whether IL-4 directs bone marrow progenitor cells to differentiate into innate Th2-type effector cells via a GATA3-dependent mechanism; and In Aim 3, we will determine whether IL-5 directs bone marrow progenitor cells to differentiate into Th2-type innate effector cells via a STAT5/GATA1-dependent mechanism. These studies will identify novel aspects of interaction between adaptive immunity and innate cells. For diseases such as allergic inflammation, asthma, parasitic infection, and other immune dysregulations, our findings could lead to more effective treatments.
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