Human innate lymphoid cells
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 ātype-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. CD56brightCD16ā cells and CD56dimCD16+ cells, that differ in terms of phenotype, effector function, and tissue localization. CD56dim cells account for ā90% 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 āSpecial Program Molecular Clinical Oncology 5Ā ĆĀ 1000ā project n.9962 (L.M.). Ministero della Salute: RO strategici 8/07 (M.C.M.).
References (90)
- et al.
Development, differentiation, and diversity of innate lymphoid cells
Immunity
(2014) - et al.
Innate lymphoid cells: new insights into function and development
Curr. Opin. Immunol.
(2015) - et al.
Innate lymphoid cells in inflammation and immunity
Immunity
(2014) - et al.
Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells
Immunity
(2013) - et al.
Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis
J. Invest. Dermatol.
(2014) - et al.
Identification of diverse innate lymphoid cells in human decidua
Mucosal Immunol.
(2015) - et al.
IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo
Immunity
(2001) - et al.
Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR(+) ILC3 in lesional skin and blood of psoriasis patients
J. Invest. Dermatol.
(2014) - et al.
The prostaglandin D2 receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung
Mucosal Immunol.
(2015) Fate and function of lymphoid tissue inducer cells
Curr. Opin. Immunol.
(2005)
Microbial flora drives interleukin 22 production in intestinal NKp46(+) cells that provide innate mucosal immune defense
Immunity
CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut
Immunity
Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease
Immunity
RORgammat(+) innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44
Immunity
Development of IL-22-producing NK lineage cells from umbilical cord blood hematopoietic stem cells in the absence of secondary lymphoid tissue
Blood
Lineage relationships of human interleukin-22-producing CD56+ RORgammat+ innate lymphoid cells and conventional natural killer cells
Blood
Human RORgammat(+)CD34(+) cells are lineage-specified progenitors of group 3 RORgammat(+) innate lymphoid cells
Immunity
Identification of a human natural killer cell lineage-restricted progenitor in fetal and adult tissues
Immunity
A human CD34(+) subset resides in lymph nodes and differentiates into CD56bright natural killer cells
Immunity
Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset
Immunity
Characterization of dendritic cell differentiation pathways from cord blood CD34(+)CD7(+)CD45RA(+) hematopoietic progenitor cells
Blood
Human NK cells at early stages of differentiation produce CXCL8 and express CD161 molecule that functions as an activating receptor
Blood
Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue
Immunity
Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH 17 cytokine interleukin-22
Blood
Differentiation of natural killer (NK) cells from human primitive marrow progenitors in a stroma-based long-term culture system: identification of a CD34Ā +Ā 7+ NK progenitor
Blood
Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells
Blood
Flt3 ligand promotes the generation of a distinct CD34(+) human natural killer cell progenitor that responds to interleukin-15
Blood
The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells
Immunity
The transcription Factor AHR prevents the differentiation of a stage 3 innate lymphoid cell subset to natural killer cells
Cell Rep.
Interleukin-12 and -23 control plasticity of CD127(+) group 1 and group 3 innate lymphoid cells in the intestinal lamina propria
Immunity
Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease
Blood
Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus?
Blood
The unexpected effect of cyclosporin A on CD56Ā +Ā CD16- and CD56Ā +Ā CD16+ natural killer cell subpopulations
Blood
The 3 major types of innate and adaptive cell-mediated effector immunity
J. Allergy Clin. Immunol.
Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors: II. Characterization of effector cells
Int. J. Cancer
Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function
Cytometry A
CD56(bright) perforin(low) noncytotoxic human NK cells are abundant in both healthy and neoplastic solid tissues and recirculate to secondary lymphoid organs via afferent lymph
J. Immunol.
T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow
J. Exp. Med.
Cutting edge: salivary gland NK cells develop independently of Nfil3 in steady-state
J. Immunol.
Unique Eomes+ NK cell subsets are present in uterus and decidua during early pregnancy
Front. Immunol.
Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues
Nat. Immunol.
Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells
J. Immunol.
Innate production of T(H) 2 cytokines by adipose tissue-associated c-Kit(+) Sca-1(+) lymphoid cells
Nature
Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity
Nature
Systemically dispersed innate IL-13-expressing cells in type 2 immunity
Proc. Natl. Acad. Sci. U. S. A.
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