Group 2 innate lymphoid cells and regulatory T cells: novel sources and targets of interleukin-4 in immunity to Heligmosomoides polygyrus

Intestinal helminth infections cause a significant global burden due to gaps in our translation of anti-helminth immunity. Immune responses to helminth infections are characterised by a balance between regulatory and effector cells, limiting immune-driven pathology in the host whilst enabling long-term survival of the parasite. Functional immunity to helminths is dependent on the activation of a type-2 immune cascade comprised of immune and non-immune cells that coordinate to promote the mechanistic expulsion of the parasite. The natural murine helminth Heligmosomoides polygyrus establishes chronic intestinal infections that can be expelled following secondary infection in drug-cured mice, and provides a good experimental model to test mechanisms of functional immunity. Immunity to H. polygyrus is dependent on the differentiation of IL-4 producing CD4+ T helper 2 cells, however the exact mechanisms required for Th2 differentiation in vivo remain unclear. In this study we have identified two novel mechanisms required for Th2 differentiation in vivo. Firstly, we identified that group 2 innate lymphoid cells (ILC2) are an important source of IL-4 for the differentiation of Th2 cells in vitro and in vivo during a chronic infection with H. polygyrus. Secondly, we have found that Foxp3+ Treg cells convert to Th2 cells and contribute significantly to memory Th2 responses following a challenge infection with Heligmosomoides polygyrus. Using a fate-reporter mouse, we have deleted IL-4Rα on Foxp3-expressing cells to test whether IL-4 receptor signalling is required for the development of ex-Foxp3 Th2 cells and whether they contribute to functional immune responses. In summary, we have characterised ILC2s and Treg cells as novel sources and targets of IL-4 required for the differentiation of Th2 cells and propose a model whereby ILC2-derived IL-4 provides a source of IL-4 for the reprogramming of Treg cells in the tissue, ultimately supporting the expulsion of H. polygyrus