Final Report Summary - ASTHMAVIR (The roles of innate lymphoid cells and rhinovirus in asthma exacerbations)
Innate Lymphoid Cells (ILCs) are emerging as coordinators of early eradication of pathogens and contributors to tissue homeostasis, repair of damage and remodelling, features that are dysfunctional in patients suffering inflammatory autoimmune diseases. We hypothesized that pathogens directly or indirectly stimulate ILCs to produce cytokines driving the effector functions leading to the end organ effects that characterize inflammatory diseases of the airways and other barrier surfaces. The project focused on identification of human ILC populations on how these cells develop and on how these cells function in healthy tissues and tissues that are affected in inflammatory autoimmune diseases of the airways, intestine and skin. The ILC family consist of 5 canonical populations, Natural Killer (NK) cells, ILC1, ILC2, ILC3 and Lymphoid tissue inducer (LTi) cells. Within these canonical populations we identified and characterized several novel subsets. In addition, we found a new marker for human LTi cells which will facilitate more detailed study of these cells. These so-called helper ILCs can acquire suppressor activities. ILC3s that express the ATP and ADP hydrolysing enzymes CD39 and/or CD73 were present in tissues but not in the circulations and these cells were able to inhibit T cell responses in vitro by converting ATP into suppressive adenosine. In addition, we found that ILC2 produce large amounts of the immune suppressant IL-10 when stimulated in the presence of retinoic acid which suppress antigen-specific T cell responses. We conclude that helper ILCs can convert to cells that have immune suppressor activities under influence of certain signals from their microenvironment.
We established that ILCs present in the peripheral blood are immature. Several novel populations of these immature ILC were identified on basis of expression of cKit, KRLG1 and NKp46 and characterized in detail by single cell flow cytometry, clonal culture techniques and analysis of transcriptomes. These cells may migrate to tissues were they further mature in fully functional tissue ILCs.
ILCs are highly flexible cells capable of rapidly changing their functional output depending on signals they receive from the tissue microenvironment they reside in. ILC3 and ILC2 can both change into inflammatory ILC1, a process driven by the cytokine IL-12. ILC3 to ILC1 conversion was observed in several inflammatory diseases including Crohn’s disease and Chronic Obstructive Pulmonary Disease (COPD). Other cytokines can induce ILC3 features in ILC1 and ILC2. Transdifferentiation of ILC2 into ILC3 was observed in nasal polyps of Cystic Fibrosis patients. Interestingly conversion of ILC2 into IL-17 producing ILC3s was also observed in inflamed plaques of patients suffering Psoriasis, a disease caused by excessive production of IL-17 in the skin and it is tempting to hypothesise that the transdifferentiated ILC are an important source of disease-causing IL-17. Thus, transdifferentiation allows ILC to adapt upon changing conditions in the microenvironment caused by pathogens. For instance, in the gut ILC3 which support homeostasis of the gut tissue can convert to inflammatory ILC1 in response to an inflammation and convert back to ILC3 when the inflammation is resolved, a process regulated by subsets of DC/macrophages. In chronic inflammatory diseases transdifferentiated cells may be dysregulated thereby contributing to maintenance of the inflammation.
Investigating DC that might interact with ILCs we found a DC population in tissues but not in peripheral blood that bears similarity to ILC in expressing CD127 and CD161. A proportion of these CD127+ DC expressed the transcription factor AutoImmune REgulator (AIRE). Since tissue-specific antigens are not present in the AIRE+ DC these cells are not involved in induction of peripheral tolerance towards these self antigens. The function of this novel DC population remains to be elucidated.
We established that ILCs present in the peripheral blood are immature. Several novel populations of these immature ILC were identified on basis of expression of cKit, KRLG1 and NKp46 and characterized in detail by single cell flow cytometry, clonal culture techniques and analysis of transcriptomes. These cells may migrate to tissues were they further mature in fully functional tissue ILCs.
ILCs are highly flexible cells capable of rapidly changing their functional output depending on signals they receive from the tissue microenvironment they reside in. ILC3 and ILC2 can both change into inflammatory ILC1, a process driven by the cytokine IL-12. ILC3 to ILC1 conversion was observed in several inflammatory diseases including Crohn’s disease and Chronic Obstructive Pulmonary Disease (COPD). Other cytokines can induce ILC3 features in ILC1 and ILC2. Transdifferentiation of ILC2 into ILC3 was observed in nasal polyps of Cystic Fibrosis patients. Interestingly conversion of ILC2 into IL-17 producing ILC3s was also observed in inflamed plaques of patients suffering Psoriasis, a disease caused by excessive production of IL-17 in the skin and it is tempting to hypothesise that the transdifferentiated ILC are an important source of disease-causing IL-17. Thus, transdifferentiation allows ILC to adapt upon changing conditions in the microenvironment caused by pathogens. For instance, in the gut ILC3 which support homeostasis of the gut tissue can convert to inflammatory ILC1 in response to an inflammation and convert back to ILC3 when the inflammation is resolved, a process regulated by subsets of DC/macrophages. In chronic inflammatory diseases transdifferentiated cells may be dysregulated thereby contributing to maintenance of the inflammation.
Investigating DC that might interact with ILCs we found a DC population in tissues but not in peripheral blood that bears similarity to ILC in expressing CD127 and CD161. A proportion of these CD127+ DC expressed the transcription factor AutoImmune REgulator (AIRE). Since tissue-specific antigens are not present in the AIRE+ DC these cells are not involved in induction of peripheral tolerance towards these self antigens. The function of this novel DC population remains to be elucidated.