The balance of power: innate lymphoid cells in tissue inflammation and repair

Abstract

Over the last ten years, immunologists have recognized the central importance of an emerging group of innate lymphoid cells (ILCs) in health and disease. Characterization of these cells has provided a molecular definition of ILCs and their tissue-specific functions. Although the lineage-defining transcription factors, cytokine production, and nomenclature parallel those of T helper cells, ILCs do not require adaptive immune programming. Both environmental and host-derived signals shape the function of these evolutionarily ancient cells, which provide pathogen protection and promote tissue restoration. As such, ILCs function as a double-edged sword, balancing the inflammatory and reparative responses that arise during injury and disease. This Review highlights our recent understanding of tissue-resident ILCs and the signals that regulate their contribution to inflammation and tissue repair in health and disease.

Figure 1. Tissue ILCs limit inflammation and promote restoration.

ILCs serve as central mediators limiting inflammation from infectious and environmental triggers. Dietary as well as neuronal factors coordinate the response of ILC2s and ILC3s in the lamina propria. LTi cells play a critical role in restoring lymphoid tissue following viral infection. AREG, IL-22, and PCTR1 promote tissue repair and limit the impact of inflammation in the tissue. AIEC, adherent-invasive E. coli; GFL, GDNF family ligands; SMC, smooth muscle cell.

Figure 2. Tissue ILCs in chronic inflammation.

Sustained activation of ILC effector functions promote inflammation. Restorative functions of IL-22 can lead to aberrant epithelial proliferation and IL-18 production to sustain an inflammatory Th1 response. ILC2 responses recruit eosinophil effectors, trigger smooth muscle contraction, and promote fibrosis.

Figure 3. ILCs balance inflammatory and reparative adaptive immunity.

LTi cells play a critical role in maintaining mucosal and systemic antibody production. MHC II⁺ ILC3s can limit the response of commensal-reactive T cells at steady state, but increases in TL1A or IL-1β can promote the activation of local and systemic inflammatory T cells, respectively. IL-33 induction of OX40L by ILC2s can support tissue Th2 and Treg responses.