Innate lymphoid cells control signaling circuits to regulate tissue-specific immunity

Abstract

The multifaceted organization of the immune system involves not only patrolling lymphocytes that constantly monitor antigen-presenting cells in secondary lymphoid organs but also immune cells that establish permanent tissue-residency. The integration in the respective tissue and the adaption to the organ milieu enable tissue-resident cells to establish signaling circuits with parenchymal cells to coordinate immune responses and maintain tissue homeostasis. Innate lymphoid cells (ILCs) are tissue-resident innate immune cells that have a similar functional diversity to T cells including lineage-specifying transcription factors that drive certain effector programs. Since their formal discovery 10 years ago, it has become clear that ILCs are present in almost every tissue but strongly enriched at barrier surfaces, where they regulate immunity to infection, chronic inflammation, and tissue maintenance. In this context, recent research has identified ILCs as key in orchestrating tissue homeostasis through their ability to sustain bidirectional interactions with epithelial cells, neurons, stromal cells, adipocytes, and many other tissue-resident cells. In this review, we provide a comprehensive discussion of recent studies that define the development and heterogeneity of ILC populations and their impact on innate and adaptive immunity. Further, we discuss emerging research on the influence of the nervous system, circadian rhythm, and developmental plasticity on ILC function. Uncovering the signaling circuits that control development and function of ILCs will provide an integrated view on how immune responses in tissues are synchronized with functional relevance far beyond the classical view of the role of the immune system in discrimination between self/non-self and host defense.

Fig. 1. Development of ILCs.

The hematopoietic stem cell (HSC) is the source of all hematopoietic cells and give rise to the common myeloid progenitor (CMP) and common lymphoid progenitor (CLP), and CLP has the potential to develop into all lymphocytes. The early ILC progenitor (EILP) gives rise to all ILC subsets, whereas common helper-like ILC progenitor (CHILP) and the ILC progenitor (ILCP) still have multi-lineage potential but this is restricted to ILC1, ILC2, and ILC3 as indicated by arrows. Transcriptional requirements, phenotypical markers, and effector molecules of ILCs are shown (TCR T cell receptor, BCR B cell receptor).

Fig. 2. Regulation of NK-cell activation.

NK cells are regulated by recognition of non-self, missing-self, and induced-self ligands. Receptor-ligand interactions and factors regulating NK-cell activation as well as effector functions are shown. MNP mononuclear phagocyte, DC dendritic cell, GR glucocorticoid receptor (Nr3c1), ADCC antibody-dependent cellular cytotoxicity.

Fig. 3. Immunoregulation mediated by ILC1s.

Multiple interactions between ILC1 and hematopoietic or parenchymal cells are depicted. MF macrophage, DC dendritic cell, MCMV murine cytomegalovirus, GR glucocorticoid receptor (Nr3c1).

Fig. 4. ILC2s regulate type 2 inflammation in tissues.

ILC2s maintain interactions between neurons, epithelial cells, stromal cells, adipocytes but also myeloid cells and adaptive lymphocytes to regulate tissue homeostasis. Baso basophil granulocyte, Eos eosinophil granulocyte, MF macrophage, DC dendritic cell, SC stromal cell, AAM alternatively activated macrophage, AR androgen receptor, AHR aryl hydrocarbon receptor, Arnt nuclear translocator of AHR, RAR retinoic acid receptor, RXR retinoid X receptor, Arg1 arginase, IgA immunoglobulin A, EC epithelial cell, GC goblet cell, TC tuft cell.

Fig. 5. Immune regulatory functions of ILC3s.

Regulatory circuits that involve ILC3s include interaction with myeloid cells, epithelial cells, stromal cells, neurons, and adaptive lymphocytes. Although depicted as one cell, it should be noted that CCR6⁺ ILC3s and CCR6⁻ ILC3s are developmentally and functionally distinct. MNP mononuclear phagocyte, 7α,25 OHC 7α25-hydroxycholesterol, M macrophage, SC stromal cell, EC epithelial cell, ISC intestinal stem cell, AHR aryl hydrocarbon receptor, Arnt nuclear translocator of AHR, RAR retinoic acid receptor, RXR retinoid X receptor, SCFA short chain fatty acid.