Research over the last 7 years has led to the formal identification of innate lymphoid cells (ILCs), increased the understanding of their tissue distribution and has established essential functions of ILCs in diverse physiological processes. These include resistance to pathogens, the regulation of autoimmune inflammation, tissue remodeling, cancer and metabolic homeostasis. Notably, many ILC functions appear to be regulated by mechanisms distinct from those of other innate and adaptive immune cells. In this Review, we focus on how group 2 ILC (ILC2) and group 3 ILC (ILC3) responses are regulated and how these cells interact with other immune and non-immune cells to mediate their functions. We highlight experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease.

Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis

Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy.

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Innate lymphoid cells: A new paradigm in immunology

Immuno-oncology is an emerging field that has revolutionized cancer treatment Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies

Natural killer cells and other innate lymphoid cells in cancer.

The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet + IFN-γ–producing group 1 ILCs (ILC1 and natural killer cells), CD8 + cytotoxic T cells (T C 1), and CD4 + T H 1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3 + ILC2s, T C 2 cells, and T H 2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid–related orphan receptor γt + ILC3s, T C 17 cells, and T H 17 cells producing IL-17, IL-22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases.

Isabelle Ommert

Papers

RORγt+ Innate Lymphoid Cells Acquire a Proinflammatory Program upon Engagement of the Activating Receptor NKp44