Elsevier

Immunology Letters

Volume 179, November 2016, Pages 2-8
Immunology Letters

Human innate lymphoid cells

https://doi.org/10.1016/j.imlet.2016.01.007Get rights and content

Highlights

  • ā€¢

    ILC1, ILC2, and ILC3 have been identified in humans.

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    The NK- and ILC3-committed precursors have been identified.

  • ā€¢

    Eomes+ NK cell differentiation is supported by IL-15.

  • ā€¢

    RORĪ³t+ ILC3 differentiation is supported by SCF, IL-7, and AhR.

Abstract

The interest in innate lymphoid cells (ILC) has rapidly grown during the last decade. ILC include distinct cell types that are collectively involved in host protection against pathogens and tumor cells and in the regulation of tissue homeostasis. Studies in mice enabled a broad characterization of ILC function and of their developmental requirements. In humans all mature ILC subsets have been characterized and their role in the pathogenesis of certain disease is emerging. Nonetheless, still limited information is available on human ILC development. Indeed, only the cell precursors committed toward NK cells or ILC3 have been described. Here, we review the most recent finding on human mature ILC, discussing their tissue localization and function. Moreover, we summarize the available data regarding human ILC development.

Introduction

Innate lymphoid cells (ILC) are a heterogeneous population of cells that have been a subject of intense research during the past few years. ILC are innate lymphocytes that, unlike adaptive T and B lymphocytes do not express rearranged antigen specific receptors [1]. ILC effector function and transcription factor requirement partially resemble those of T lymphocytes [2]. Accordingly, ILC have been classified into killer-ILC and helper-ILC that mirror CD8+ cytotoxic T cells and CD4+ T helper cells, respectively [1]. Killer-ILC are represented by natural killer (NK) cells, the first ILC subset identified already in the 1970s [3]. NK cells display cytolytic activity and produce cytokines, primarily IFNĪ³, and mediate host defences against both tumor and virus-infected cells. NK cells express Eomesodermin (Eomes) and T-box transcription factor T-bet, required for their development and function. Helper-ILC are further classified into ILC1, ILC2, and ILC3. ILC1 express T-bet and secrete IFNĪ³, but different from NK cells, do not exert cytolytic activity. ILC1 have been shown to be involved in responses against protozoa and intracellular bacteria. ILC2 depend, for their development, on expression of GATA binding protein 3 (GATA3) and produce primarily IL-13 and IL-5. They contribute to the defence against helminthes and are involved in allergic responses. Finally, ILC3 express the retinoic acid receptor related orphan receptor (RORĪ³t) and produce ā€œtype-17ā€ cytokines, mainly IL-17 and IL-22. ILC3 include fetal lymphoid inducer (LTi) cells, which drive secondary lymphoid organ development during embryogenesis, and post-natal ILC3 that are involved in tissue homeostasis and defence against extracellular pathogens. The majority of studies that allowed the characterization of ILC function and development have been performed in mice [1], [4], [5]. Here we will review our current knowledge on ILC tissue distribution, function and development in humans.

Section snippets

NK cells vs ILC1

NK cells were the first ILC subset to be identified. Accordingly, they are the most widely characterized ILC population [6]. While helper-ILC are scarcely represented in peripheral blood (PB), NK cells may represent up to 15% of peripheral blood (PB) lymphocytes. NK cells include two main subsets, i.e. CD56brightCD16āˆ’ cells and CD56dimCD16+ cells, that differ in terms of phenotype, effector function, and tissue localization. CD56dim cells account for ā‰ˆ90% of PB NK cells. CD56dim NK cells

ILC development in humans

Studies in mice, that can take advantage of fate mapping or knocking out of selected genes, allowed the elucidation of murine ILC developmental relationships. In particular, analysis of the origin of murine ILC allowed the identification of transcription factors, cytokine and environmental signals driving the differentiation of distinct subsets. The characterization of the ILC developmental hierarchy indicate that differentiation proceeds from the common lymphoid progenitor (CLP), then diverge

Concluding remarks

The past few years have witnessed a broad interest in ILC development and lineage relationships. However, further elucidation of the human ILC differentiation hierarchy is required. Indeed, the existence of a common-helper ILC precursor is yet to be defined. Moreover, although ILC2 could be generated in vitro [53], [56], the identification of the ILC2 committed precursor and of the signals driving an efficient ILC2 differentiation is still lacking. Furthermore, important questions regarding the

Conflict of interest disclosure

The authors declare no conflict of interest.

Acknowledgments

This work was supported by Associazione Italiana per la Ricerca sul Cancro - AIRC: IG2010 project n.10225 (L.M.), IG2014 project n.15283 (L.M.), and ā€œSpecial Program Molecular Clinical Oncology 5Ā Ć—Ā 1000ā€ project n.9962 (L.M.). Ministero della Salute: RO strategici 8/07 (M.C.M.).

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