Recent evidence shows that innate lymphoid type 2 cells (ILC2s) through production of IL-13 and IL-5 are critical in airway pathologies and tissue damage, strongly correlated with severe asthma. ILC2s not only produce IL-5 and IL-13, but also the epidermal growth factor amphiregulin, which promotes tissue remodeling and lung homeostasis following influenza infection. For developing therapeutic strategies to specifically target ILC2-mediated inflammation, while maintaining tissue repair activity, it is of crucial importance to delineate regulatory mechanisms involved in ILC2 development, maintenance and function. Our preliminary data demonstrate that Bcl11b is highly expressed in ILC2 cells in the periphery, as well as in bone marrow precursors. Induced removal of Bcl11b causes loss of their identity. Bcl11b-/- ILC2 population showed reduced IL-5 production following papain-induced lung inflammation, resulting in diminished eosinophil and increased neutrophil recruitment to the lung. Additionally, numbers of ILC2s were overall reduced in the bone marrow. In this grant application we propose to establish the role of Bcl11b in ILC2s lineage determination, in mature ILC2 cell function and identity and determine the mechanisms by which Bcl11b controls ILC2 genetic program.
Recent evidence shows that innate lymphoid type 2 cells (ILC2s) through production of IL-13 and IL-5 are critical in airway pathologies and tissue damage, strongly correlated with severe asthma. The studies proposed here have major relevance for understanding the control of ILC2 genetic program, their development, identity and function. Understanding the biology of ILC2s is of major impact and importance for developing treatments to control the destructive behavior of ILC2s, while maintaining their ability to support lung tissue homeostasis. These studies have high impact on future development of therapies to promote protection from inflammatory diseases, including asthma and influenza.
|Uddin, Mohammad Nizam; Sultana, Dil Afroz; Lorentsen, Kyle J et al. (2016) Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival. Proc Natl Acad Sci U S A 113:7608-13|
|Califano, Danielle; Cho, Jonathan J; Uddin, Mohammad N et al. (2015) Transcription Factor Bcl11b Controls Identity and Function of Mature Type 2 Innate Lymphoid Cells. Immunity 43:354-68|