Innate lymphoid cells (ILCs)

Location: Blood, Lymphoid tissues, Non-lymphoid tissue

Innate lymphoid cells (ILCs) are a distinct group of immune cells that, while lacking antigen-specific receptors, exhibit functional and phenotypic similarities to CD4+ T helper (Th) cells. These similarities are reflected in the classification of ILCs into three main groups: Group 1 ILCs (ILC1) resemble Th1 cells, Group 2 ILCs (ILC2) mirror CD4+ Th2 cells, and Group 3 ILCs (ILC3) are akin to T helper 17 cells.

Innate lymphoid cells (ILCs) are characterized by their lack of clonally distributed diverse antigen receptors, a feature primarily due to the absence of the recombination-activating (rag) genes. This absence is a defining trait of ILCs, setting them apart from B or T cells which possess antigen-specific receptors. Additionally, ILCs do not express receptors that respond to and 'remember' specific pathogens, distinguishing them further from the adaptive immune response elements.

Despite the absence of a universally definitive marker for ILCs, they are generally identified as CD3-negative lymphocytes that express the Interleukin-7 (IL-7) receptor (CD45+ CD3− CD127+ ). However, it's noteworthy that in many tissues, Group 1 ILCs (ILC1) do not express CD127 (Interleukin-7 receptor-alfa)

Innate lymphoid cells (ILCs) express various transcription factors and cytokines that align with those of T helper cells, which has led to their categorization based on lineage-defining transcription factors and characteristic cytokine production. These cells are divided into the non-cytotoxic helper ILCs, which include ILC1, ILC2, and ILC3. Notably, ILCs show high expression of CD127 (Interleukin-7 receptor-alfa), except for certain ILC1 populations.

A universal nomenclature proposed in 2018 expanded the classification of Innate lymphoid cells (ILCs) into five subgroups: natural killer cells (NK cells), Group 1 ILCs (ILC1), Group 2 ILCs (ILC2), Group 3 ILCs (ILC3), and Lymphoid Tissue Inducer Cells (LTi cells). Among these, only Natural killer cells (NK cells) and Group 1 ILCs (ILC1) exhibit cytotoxic activity. NK cells specifically express the transcription factor Nuclear Factor, Interleukin-3 Regulated (NFIL3)

Innate lymphoid cells (ILCs) originate from Common innate lymphoid progenitor cells (CILPs) and are primarily stimulated by stress signals similar to those that activate neutrophils, macrophages, and dendritic cells (DCs). These stimuli include opsonized microbes, foreign antigens, and cytokines, highlighting the innate immune response capabilities of ILCs.

In summary, innate lymphoid cells are crucial components of the immune system, mirroring the functions of T helper cells but operating within the innate immune response framework. Their unique characteristics and responses play a pivotal role in the body's defense mechanisms against various pathogens.

References:
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Meininger et al. 2020 Trends in Immunology 41: 902
Clottu et al. 2022 Front. Immunol. 12: 789788
Willey et al. 2023 McGraw Hill, USA, ISBN 978-1-265-12303-1

The list of agonists for Innate lymphoid cells (ILCs) is expanding. How these signals interact is unclear, especially in vivo. Innate lymphoid cells (ILCs) subsets and T helper (Th) cells share traits. They have similar transcription factors, chromatin landscapes, and cytokines. ILC agonists are grouped by the transcription factors they activate. The signals that activate Innate lymphoid cells (ILCs) effector functions can be organized into four groups based on the transcription factors that they mobilize:
(1) Signal transducer and activator of transcription 5 (STAT5);
(2) Signal transducer and activator of transcription 6 (STAT6);
(3) NF kappa B (NFKB) / NFKB Family / Activator protein 1 / Transcription Factor AP-1 (AP-1); and
(4) Nuclear Factor of Activated T-Cells (NFAT) / Activator protein 1 / Transcription Factor AP-1 (AP-1).
McGinty & von Moltke 2020

In studies conducted on mice, it is becoming increasingly evident that the pool of innate lymphoid cells (ILCs) present in a specific tissue is the outcome of successive waves of development occurring from fetal stages to adult life. This process has been referred to as layered ontogeny.
Schneider et al. 2019a Immunity 50: 1425-1438
Oherle et al. 2020 Immunity 52: 275-294

Innate lymphoid cells (ILCs) are a diverse group of lymphocytes that do not possess rearranged antigen receptors. They play a crucial role in the immune system by responding to various insults through the production of cytokines, which are essential for initiating immune responses and facilitating tissue repair.
Klose & Artis 2016 Nat. Immunol. 17: 765-774
Simoni et al. 2017 Immunity 46: 148-161
Vivier et al. 2018
Sonnenberg & Hepworth 2019 Nat Rev Immunol 19: 599-613
Bal et al. 2020 Nat Rev Immunol 20: 552-565

There is evidence suggesting that the local pool of innate lymphoid cells (ILCs) can be at least partially replenished through the infiltration and in situ differentiation of circulating naïve ILCs, which are referred to as innate lymphoid cell precursors (ILCP).
Lim et al. 2017 Cell 168: 1086-1100
Nagasawa et al. 2019 J Exp Med 216: 1762-1776

Innate lymphoid cells (ILCs) are primarily found within tissues, especially in mucosal linings. In these locations, they may serve functions that are either protective to the tissue or contribute to inflammation.
Vivier et al. 2018

Parabiosis experiments conducted on mice have shown that innate lymphoid cells (ILCs), rather than natural killer (NK) cells, primarily reside within tissues as immune cells (Gasteiger et al. 2015 Science 350: 981-985), even during inflammatory conditions. However, this concept has been contested by other studies (Huang et al. 2018 Science 359: 114-119)

The microbiome shapes the spectrum and regulatory landscape of intestinal innate lymphoid cells.
Gury-BenAri et al. 2016 Cell 166: 1231-1246

see also:
Group 1 ILCs (ILC1)
Group 3 ILCs (ILC3) & Intestinal Mucosal Barrier / Mucus Layer
Gut microbiota & Immunity
Gut microbiota & Innate lymphoid cells (ILCs)
Innate lymphoid cells (ILCs) & Tissue repair
Innate Lymphoid Cell Precursors (ILCP)
TCRgamma/delta+ IELs