Review

Innate lymphoid cells: A new paradigm in immunology

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Science  22 May 2015:
Vol. 348, Issue 6237, aaa6566
DOI: 10.1126/science.aaa6566

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Cells acting at the intersection of immunity

For years, scientists divided the immune system into two arms: innate and adaptive. The cell types involved in the two arms differ in specificity and in how quickly they respond to infections. More recently, immunologists discovered a family of immune cells termed “innate lymphoid cells,” which straddle these two arms. Eberl et al. review current understanding of innate lymphoid cells. Like innate immune cells, they respond to infection quickly and do not express antigen receptors; however, they secrete a similar suite of inflammatory mediators as T lymphocytes. Better understanding of the processes regulating these cells may allow for their therapeutic manipulation.

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Structured Abstract

BACKGROUND

Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. Natural killer (NK) cells can be considered the innate counterparts of cytotoxic CD8+ T cells, whereas ILC1s, ILC2s, and ILC3s may represent the innate counterparts of CD4+ T helper 1 (TH1), TH2, and TH17 cells. However, in contrast to T cells, ILCs do not express 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. Thus, the power of ILCs may be controlled or unleashed to regulate or enhance immune responses in disease prevention and therapy.

ADVANCES

As with B cells and T cells, ILCs develop from the common lymphoid progenitor, but dedicated transcription factors supress the B and T cell fates and direct the generation of the different types of ILCs. ILC precursors may migrate from their primary site of production into infected and injured tissues, where they complete their maturation, similar to the differentiation of naïve T cells into TH effectors. Cytokines produced by local cells as well as stress ligands and bacterial and dietary compounds regulate the maturation and activation of ILCs into effectors that play a major role in early immune responses to pathogens and symbionts, helminths, and allergen. The cytokines they produce induce innate responses in stromal, epithelial, and myeloid cells and regulate the activity of dendritic cells (DCs), which play a central role in the cross-talk between ILCs and T cells. In particular, ILCs activate tissue-resident DCs to migrate to lymph nodes, where they elicit specific T cell responses, which in turn regulate ILCs. ILCs also directly regulate T cells through the presentation of peptide antigens on major histocompatibility complex II. However, ILCs are also involved in immunopathology, during which their production of cytokines exacerbates the inflammatory process.

ILCs also play an intriguing role beyond immunity. In adipose tissues, they regulate thermogenesis and prevent local inflammation that may lead to metabolic syndrome, insulin resistance, and obesity-associated asthma. The functions of ILCs in host metabolism are a new area of research that will lead to insights into how the immune system is implicated in host functions not directly related to defense. Furthermore, ILCs are involved in repair responses upon infection and injury of epithelial cells, stromal cells, and stem cells.

OUTLOOK

A logical next step will be the identification of molecules that allow manipulation of ILCs and the orchestration of the optimal immune response after vaccination and immunotherapy—or in contrast, to block detrimental responses. The combination of a prompt activation of ILCs with both effector and regulatory functions, with the expansion of antigen-specific B and T cells, should lead to new and powerful avenues in clinical immunology.

Signals from injured or infected tissues expand and activate NK cells, ILC1s, ILC2s, and ILC3s.

The effector functions of ILCs mirror the functions of CD8+ and CD4+ T cells, with the major difference being the prompt activation of ILCs and their lack of (relatively slow) antigen-dependent clonal selection and expansion.

Abstract

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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