Asthma is a complex disorder influenced by the interaction of genetic and environmental factors such as exposure to allergens, infections, and air pollution. Excessive Th2 biased immune responses to environmental antigens are thought to cause pulmonary inflammation, airway eosinophilia, mucus hypersecretion and airway hyperreactivity (AHR), cardinal features of asthma. Recent studies have shown that regulatory T (Treg) cells play an important role in controlling the pathogenic immune responses seen in asthma, and the development of Treg cells is thought to protect against asthma. Although therapies that induce Treg cells would provide a cure for patients with asthma, little is known about how to induce Treg cells, how Treg cells develop, or how they suppress allergic immune responses. In order to improve the treatments for asthma and to develop strategies that might routinely induce Treg cells that suppress inflammation in asthma, further understanding of the mechanisms controlling the development and function of these cells is required. Preliminary experiments in our laboratory (see preliminary results section) have shown that in the absence of Ikaros, a transcription factor expressed in early T-cell progenitors as well as in mature T cells, the development of CD25+Foxp3+ Treg cells is significantly reduced. In addition, the production of IL-10, a critical cytokine normally secreted by both Treg cells and dendritic cells that induce Treg cells, is greatly reduced in Ikaros-/- T cells. This suggests that Ikaros critically regulates the development of Treg cells as well as the production of IL-10. The goal, therefore, of this proposal, is to study the role of Ikaros in the development of Treg cells that protect against allergic asthma.
In Specific Aim 1, we will examine the molecular mechanisms of Ikaros as a transcription factor that controls 1110 gene expression.
In Specific Aim 2, we will use in vitro proliferation assays to compare purified Ikaros-/- and wild type Treg cells in order to investigate if Ikaros regulates Treg cell function. Finally, in Specific Aim 3, we will examine the function of Ikaros in an in vivo mouse model of asthma, to demonstrate how lack of Ikaros in Treg cells impacts airway inflammation and AHR induced by common environmental antigens. Asthma is a complex disease that occurs due to a combination of environmental and genetic factors. The breakdown in normal regulation of the immune system is of major significance in the development of this disease. Regulatory T cells play an important role in controlling the immune response and thus, it is of therapeutic importance to further understand the mechanisms controlling regulatory T cell function.
|Agnihotri, Parul; Robertson, Nicholas M; Umetsu, Sarah E et al. (2017) Lack of Ikaros cripples expression of Foxo1 and its targets in naive T cells. Immunology 152:494-506|
|Chari, Sheila; Umetsu, Sarah E; Winandy, Susan (2010) Notch target gene deregulation and maintenance of the leukemogenic phenotype do not require RBP-J kappa in Ikaros null mice. J Immunol 185:410-7|
|Quirion, Mary R; Gregory, Gregory D; Umetsu, Sarah E et al. (2009) Cutting edge: Ikaros is a regulator of Th2 cell differentiation. J Immunol 182:741-5|
|Umetsu, Sarah E; Winandy, Susan (2009) Ikaros is a regulator of Il10 expression in CD4+ T cells. J Immunol 183:5518-25|