Innate lymphoid cell

Innate lymphoid cells (ILCs) are a group of innate immune cells that belong to the lymphoid lineage (lymphocytes) but do not respond in an antigen-specific manner, as they lack a B or T cell receptor. This relatively newly described group of cells has different physiological functions, some of them analogous to helper T cells, while also including the cytotoxic NK cells. In accordance, they have an important role in protective immunity and the regulation of homeostasis and inflammation, so their dysregulation can lead to immune pathology such as allergy and autoimmune disease.

Classification

ILCs can be divided based on the cytokines that they can produce, and the transcription factors that regulate their development and function. For each newly discovered branch of the ILC family, it will be important to determine whether a cell type represents a stable lineage or just a stage of differentiation or activation. The emerging body of data about the transcription factors and cytokine signals that differentiate ILCs contributes to the evolving classification system used to identify ILCs.

In 2013 a nomenclature and classification system was proposed that divides the known ILCs into three groups.

Group 1 ILCs

Group 1 ILCs can produce type 1 cytokines (notably IFNγ and TNF) and comprise NK cells and ILC1s:

• ILC1s are weakly cytotoxic cells closely related to ILC3s, from which they even appear to arise.
• Natural killer ('NK') cells are cytotoxic innate effector cells analogous to the cytotoxic T cells of the adaptive immune system. They are distributed throughout the blood, organs, and lymphoid tissue and make up around 15% of the peripheral blood lymphocytes. NK cells play a role in tumor surveillance and the rapid elimination of virus-infected cells. They do not require the missing “self” signal of MHC Class I and can recognize stressed cells in the absence of antibodies, allowing them to react much more quickly than the adaptive immune system. NK cells, discovered in 1975, are the prototypical innate lymphoid cell, and have been described as large granular lymphocytes that lack the T cell receptor.

Group 2 ILCs

Group 2 ILCs can produce type 2 cytokines (e.g. IL-4, IL-5, IL-9, IL-13).

ILC2s (also termed natural helper cells, nuocytes, or innate helper 2 cells ) play the crucial role of secreting type 2 cytokines in response to helminth infection. They have also been implicated in the development of allergic lung inflammation. They express characteristic surface markers and receptors for chemokines, which are involved in distribution of lymphoid cells to specific organ sites. They require IL-7 for their development, which activates two transcription factors (both required by these cells)—RORα and GATA3. ILC2s are critical for primary responses to local Th2 antigens in the lung but are dispensable for responses to systemically delivered Th2 antigens.

Group 3 ILCs

Group 3 ILCs are defined by their capacity to produce cytokines IL-17A and/or IL-22. They comprise ILC3s and lymphoid tissue-inducer (LTi) cells:

• ILC3s are a lymphoid cell population that can produce IL-22 and expresses NKp46 (an NK cell activating receptor). Nevertheless, ILC3s differ from NK cells, as they are dependent on transcription factor RORγt, they lack cytotoxic effectors (perforin, granzymes and death receptors) and they do not produce IFNγ or TNF. They are found mainly in mucosal tissues and particularly in the intestinal tract.
• Lymphoid tissue inducer ('LTi') cells are a subset of ILCs expressing molecules required for the development of lymphoid tissue. They are essential for development of lymphoid organs during embryogenesis and after birth regulate the architecture of lymphoid tissue. On top of that, they have been linked to the maintenance of T cell memory.

Development

CLPs, or common lymphoid precursors have the ability to differentiate into a number of different cell types including T cells, B cells, and ILCs depending on the cellular signals present. With the exception of NK cells, all ILCs require IL-7 signaling for survival. Transcriptional repressor ID2 appears to antagonize B and T cell differentiation, yielding an ID2-dependent precursor that can further differentiate with lineage-specific transcription factors. There is evidence that the different branches of ILCs share a common precursor. Notch signaling may also be involved in the initial differentiation to a common ILC precursor. The development of ILCs is not completely understood. ILC3s may be necessary precursors to ILC1s.

Function

ILCs are a multifunctional group of cells. Their ability to rapidly secrete immunoregulatory cytokines allows them to contribute early on in immune responses to infection. They often reside at mucosal surfaces, where they are exposed to infectious agents in the environment.

Helminth infection

ILC2 cells play a crucial role in the protection against helminthic infection. They are a major early source of IL-13, which can activate T cells and induce physiological responses that will help expel a parasite. These physiological responses include stimulating goblet cell mucus secretion and contraction of smooth muscle. In addition, they secrete signals that recruit and activate mast cells and eosinophils, and which stimulate B cell proliferation. They also secrete Amphiregulin, a member of the epidermal growth factor family, that stimulates tissue repair. This can function to enhance the barrier function of the epithelium and slow pathogen entry.

Enteric pathogens

In the environment of intestinal tract, ILC3s have a crucial role in mediating the balance between symbiotic microbiota and the intestinal immune system. In response to inflammatory signals from the dendridic cells and gut epithelium, they produce IL-22 which increase the production of antimicrobial peptides and defensins. ILC3s also assist in immune responses to extracellular bacteria by maintaining the homeostasis of epithelia. Therefore, when malfunction appears, these cells may participate in the development of inflammatory bowel diseases (IBD).

Tumor surveillance

NK cells can induce apoptosis or cell lysis in tumor cells and cell infected with a virus. Their function is regulated by a balance of stimulatory and inhibitory signals. While they do not have T cell receptors and do not necessarily require MHC class I binding, they express a number of cell surface receptors that can recognize stressed cells. For example, NKG2D is a receptor that can recognize ULBP and MICA, two surface markers that are frequently upregulated in tumor cells. In this way, they act in a complementary manner with the cytotoxic T cells that are able to very effectively kill unhealthy self cells only when presented a foreign antigen.

Pathology

Allergy and asthma

ILC2s play a variety of roles in allergy. Primarily, they provide a source of the type 2 cytokines that orchestrate the allergic immune response. They produce a profile of signals in response to pro-allergenic cytokines IL-25 and IL-33 that is similar to those produced in response to helminthic infection. Their contribution to this signaling appears to be comparable to that of T cells. In response to allergen exposure in the lungs, ILC2s produce IL-13, a necessary cytokine in the pathogenesis of allergic reactions. This response appears to be independent of T and B cells. Further, allergic responses that resemble asthma-like symptoms have been induced in mice that lack T and B cells using IL-33. It has also been found that ILC2s are present in higher concentrations in tissues where allergic symptoms are present, such as in the nasal polyps of patients with chronic rhinosinusitis and the skin from patients with atopic dermatitis.

Autoimmune disease

NK cells express many cell-surface receptors that can be activating, inhibitory, adhesion, cytokine, or chemotactic. The integration of information collected through these numerous inputs allows NK cells to maintain self-tolerance and recognize self-cell stress signals. If the nuanced, dynamic regulation of NK cell activation becomes unbalanced in favor of attacking self cells, autoimmune disease pathology. NK cell dysregulation has been implicated in a number of autoimmune disorders including multiple sclerosis, systemic lupus erythematosus, and type I diabetes mellitus.

Innate or adaptive

Historically, the distinction between the innate and adaptive immune system focused on the innate system’s nonspecific nature and lack of memory. As information has emerged about the functions of NK cells and other ILCs as effectors and orchestrators of the adaptive immune response, this distinction has become less clear. Some suggest the definition focus more on the germline-coding of receptors in the innate immune system versus the rearranged receptors of the adaptive immune system.

See also

• Innate immune system
• NK Cell