Allergic pulmonary disease is one of the leading health problems in the USA and the world. The hallmark of allergic pulmonary disease is airway inflammation caused by increased numbers of inflammatory infiltrates. Studies have shown type 2 helper T (TH2) cells and group 2 innate lymphoid cells (ILC2s), and their cytokine products play pivotal roles in allergic airway disease. How the deregulation of type 2 responses causes the disease is not well understood. Recently, we revealed a feedback loop in which Cytokine Induced SH-2 protein (CIS) antagonized IL-4 mediated STAT6 and IL-2 mediated STAT5 activation which in turn attenuated pro-allergic TH2 and TH9 cell development; mice deficient on Cis spontaneously developed spontaneous airway inflammation resembling human allergic pulmonary disease. However, mice with T cell-specific Cis-deficiency did not develop similar spontaneous disease. Therefore, other cell types with Cis- deficiency may be also essential in development of the spontaneous allergic airway symptoms. Fully understanding the role of CIS in control of allergic airway inflammation may suggest novel methods for treatment of allergic pulmonary disease. Our immediate objective is to determine how CIS targets non-T cells and controls allergic airway inflammation. Our central hypothesis is that CIS inhibits pro-allergic ILC development and in turn attenuates ILC2-driven amplification of TH2 responses, which together contribute to CIS-mediated control of allergic airway inflammation. Our current data support this hypothesis.
Specific Aims :
Aim 1. Determine the role of CIS in the development and function of ILC2s;
Aim 2. Investigate CIS signaling in ILC2s;
Aim 3. Determine the ILC2-intrinsic role of CIS in susceptibility to allergic pulmonary disease. Relevance to health: By analyzing CIS-mediated inhibition of cytokine signaling, this study will reveal a previously unknown regulatory circuit in pro-allergic ILC2s that is required for amplifying TH2 responses, whereby contributing to the control of allergic airway responses. The results will potentially provide novel insights into the pathogenesis of allergic pulmonary disease, and may suggest new therapeutic methods.
Allergic pulmonary disease including allergic asthma is one of the leading health problems in the USA and the world. However, the pathogenesis is not well understood. In our preliminary study, we found the deficiency of CIS led to spontaneous allergic lung disease in mice, resembling human allergic asthma; some unappreciated cells other than pro-allergic T cells are responsible for the induction of the spontaneous disease. In this proposal, we hypothesize that an additional subset of pro-allergic cells, termed ILC2s, plays an essential role in allergic reactions, and aim to answer the following questions: how CIS is regulated in ILC2s, what cytokine-STAT signals are disrupted by CIS, how CIS controls pro-allergic ILC2 development and how the deficiency of CIS in ILC2s leads to allergic lung disease. The results will potentially provide novel insights into the pathogenesis of allergic pulmonary disease, and may suggest new therapeutic methods to human allergic lung disease.
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