Interferon gamma-Producing Th17 Subsets: Major Contributors to "Th1" Diseases?

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Sponsor: NIH National Institute of Allergy and Infectious Disease

Location(s): United States

Description

We have recently discovered in two separate cohorts that the most prevalent immune cells producing interferonγ (IFNγ) in pulmonary sarcoidosis lung lavage are not Th1 cells but another cell which has been identified as a highly pathogenic subset of Th17 cells, called Th17.1, due to their enhanced ability to produce IFNγ among other functions. These findings challenge the Th1 paradigm that has held sway in sarcoidosis since the invention of research bronchoscopy. But more importantly, our findings have the ability to shift the research focus to these Th17.1 cells, about which we know little of their pathogenic traits and functional differences compared to Th17 cells in sarcoidosis. The literature suggests that Th17.1 cells appear to be derived from classically polarized Th17 cells which are highly “plastic” and can be stimulated to turn on Th1-related signaling pathways by proinflammatory cytokines such as IL-12. Th17.1 cells in sarcoidosis do not appear to share proliferative defects as documented for Th17 cells. We also know from Crohn's disease that Th17.1 cells exhibit corticosteroid resistance. In our data, we found a trend in correlation between worsening lung function (FEV1 % predicted) with increasing percentage of Th17.1 cells. This suggests that Th17.1 cells in sarcoidosis may contribute to disease severity but cellular mechanisms have not been explored. In addition, another distinct subset of Th17 linage cells have been identified in published studies and are called “Th17- derived Th1 cells”. These cells are thought to be even more polarized towards a Th1 phenotype than Th17.1 cells due to their loss of IL-17A secretion and marked production of IFNγ. Thus, our finding of high frequencies of Th17.1 cells in sarcoidosis raises the question of whether the cells we have long termed “Th1” in sarcoidosis could actually instead belong to this Th17-derived Th1 subset. Therefore, we hypothesize that Th17 cells are plastic and their biologic phenotype exists in a continuum from Th17→Th17.1→Th17-derived Th1 cells in the milieu of polarizing cytokines IL-12 and IFNγ found in sarcoidosis. These polarized Th17 cells have pathogenic potential to promote sarcoidal inflammation and cause progressive disease. Thus, we propose to interrogate the proliferative capacity and related functions of Th17 vs Th17.1 cells in sarcoidosis compared healthy controls and asthmatics. We will also use flow cytometry and CyTOF methods to measure the range of Th17 subsets and their ability to resist corticosteroid effects.