UCSF

MicroRNAs (miRNAs) exert powerful effects on immune function by tuning networks of target genes that orchestrate cell behavior. We sought to uncover miRNAs and miRNA-regulated pathways that control the TH2 responses that drive pathogenic inflammation in asthma. Profiling miRNA expression in human airway-infiltrating T cells revealed miR-19a elevation in asthma. Modulating miR-19 activity altered TH2 cytokine production in both human and mouse T cells, and TH2 cell responses were markedly impaired in cells lacking the entire miR-17~92 cluster. miR-19 promotes TH2 cytokine production and amplifies PI(3)K, JAK-STAT, and NF-κB signaling by direct targeting of PTEN, SOCS1, and A20. Thus, miR-19a upregulation in asthma may be an indicator and a cause of increased TH2 cytokine production in the airways.

TH2 cells are not the only lymphocyte involved in asthma pathogenesis. Other T-helper subsets, such as TH1 and TH17 cells, are present in asthmatic airways, and may be responsible for non- TH2-driven asthma. Through collaborative clinical studies, we aim to profile miRNA expression in various T-helper cells in asthmatic and healthy airways to uncover pathways involved in TH2-driven and non- TH2-driven asthma pathogenesis. This study also allows us to immunophenotype healthy and asthmatic individuals by flow cytometry of bronchoalveolar lavage fluid and peripheral blood.

Although we have focused on lymphocyte functions in asthma pathogenesis, the role of innate immune cells cannot be overlooked. Type 2 innate lymphoid cells (ILC2s) and basophils are capable of producing TH2 cytokines, and can respond to environmental cues of lung damage. Through a collaborative clinical study, we investigated the prevalence and function of ILC2s and basophils in asthma by flow cytometric immunophenotyping and gene expression of sputum cell pellets. Interestingly, ILC2s are equally rare in the sputum of healthy and asthmatic individuals, while basophils are more abundant in asthmatic individuals. The number of basophils positively correlates with sputum cell pellet expression of TH2 cytokines, and correlates with asthma severity. These findings suggest a role for basophils in polarizing the lung environment towards TH2, and increasing asthma symptoms.