Investigating functions of human group 2 innate lymphoid cells in health and disease

Group 2 innate lymphoid cells (ILC2) have emerged as important effectors of type 2 immune responses that contribute to protection against extracellular parasites and tissue repair. Dysregulated ILC2 responses have been implicated in allergic inflammatory disorders such as atopic dermatitis (AD), a chronic inflammatory skin disease associated with epidermal barrier defects and dysregulated type 2 inflammation. However, much remains to be understood regarding ILC2 effector functions, especially in the context of cutaneous inflammation. Using an in vivo human skin blister model, extensive multianalyte profiling revealed significant differences in the protein expression profile of healthy and AD skin; and skin ILC2 were found to express a range of cytokine- and chemokine-encoding genes following intradermal allergen challenge. In vitro experiments confirmed secretion of a broad range of cytokines and chemokines, including granulocyte macrophage colony-stimulating factor (GM-CSF) and the chemokines CCL22 and CCL17, by human ILC2 in response to activation by alarmin cytokines. Elevated levels of CCL22 and CCL17 were detected in both sera and skin blister fluids from individuals with AD compared to healthy controls, and increased surface expression of CCR4, the shared receptor for CCL22 and CCL17, was detected on blood ILC2 and T cells from individuals with AD. In vitro, ILC2 were found to promote recruitment of both ILC2 and T cells, directly and indirectly through induction of monocyte-derived dendritic cell (moDC) chemokine production, involving CCL22 and CCL17. Thus, ILC2 may contribute to AD pathogenesis by promoting the accumulation of CCR4+ ILC2 and Th2 cells. Moreover, through GM-CSF secretion, human ILC2 were identified as inducers of monocyte differentiation into CD1a+ moDC, resembling in vivo inflammatory moDC. ILC2-induced moDC were capable of activating CD1a-reactive T cells, resident in healthy skin and increased in abundance in AD skin. Taken together, this study identified previously unrecognised roles of human ILC2 in the chemotactic recruitment of ILC2 and T cells and as inducers of moDC differentiation with implications for cutaneous inflammation.