Down-regulation of E protein activity augments an ILC2 differentiation program in the thymus

Abstract

Abstract Innate lymphoid cells (ILCs) have gained recognition as important regulators in various immune responses. How these cells are generated is just beginning to be understood. Current paradigm states that all three subsets of ILCs originate from common lymphoid progenitors (CLP) in the bone marrow through an array of downstream ILC progenitors. Id2, a member of the Id family that inhibits the function E protein transcription factors, is expressed in these ILC progenitors and is indispensable for ILC differentiation. Unexpectedly, we found that specifically down-regulating E protein function in the thymus by either Id1 expression or conditional deletion of two E protein genes resulted in massive expansion of ILC2s in the thymus as well as other organs where ILC2 normally reside. Consequently, the mutant mice exhibit augmented spontaneous infiltration of eosinophils and heightened responses to allergen, papain, in the lung. Furthermore, these mice also display increased ability in the expulsion of helminth parasites, N. Brasiliensis. These results raise an interesting question as to whether the thymus is a natural site for ILC2 production and the phenotypes of our mutant mice simply highlight such capacity. Indeed, lineage tracing experiments using lck-Cre/ROSA26-stop-tdTomato mice demonstrate that tdTomoto specifically marks a fraction of ILC2s in the thymus as well as in the lung, suggesting that thymus-derived ILC2s preferentially home to the lung. We also found that thymic progenitors were able to differentiate into ILC2 cells in vitro. Together, our data reveal a new ILC2 differentiation program present in the thymus, which enriches our knowledge about ILC2 ontogeny and has potential biological significance.