Innate lymphoid cells

Heterogeneous family of cells of the innate immune system that morphologically resemble lymphocytes (hence the term "lymphoid"), but in contrast to lymphocytes do not express their typical surface markers(CD4, CD8, CD19, CD20) and thus act independently of antigens. Their existence has only been known for a few years. Innate lymphoid cells (ILCs) do not carry antigen-specific receptors on their surface. They also do not circulate through the bloodstream but are sessile cells. ILCs therefore belong to the local organ tissue.

ILCs are formed locally as required and are only replenished from the progenitor cells located in the bone marrow during chronic processes. They are important players in the innate immune system and play a central role in the defence against infectious agents. The reaction of the immune system to allergens is also influenced by subgroups of the ILC.

In analogy to T helper cells and on the basis of their cytokine spectrum and their transcription factors essential for development, ILCs can be divided into three groups:

• Group 1 ILC (ILC1)
• Group 2 ILC (ILC2)
• Group 3 ILC (ILC3)

Group 1 ILC

Group 1 ILCs produce the pro-inflammatory cytokine interferon (IFN)-γ and are dependent on the transcription factors T-bet, Eomes and/or RORgt. This group includes NK cells(natural killer cells). By releasing perforin and proteases (e.g. granzymes) from granules, NK cells exert a cytotoxic effect on their target cells.

Group 2 ILC

The key cytokines of group 2 ILCs, also known as ILC2, are IL-5 and IL-13. Until recently, the ILCs of this group were referred to under several names ("Natural Helper Cells", "Nuo cytes" and "Innate Helper 2"). They are found in the intestine, mesenteric lymph nodes, lungs, spleen, liver and also in the skin. ILC2 play a protective role in the early defense against yeast and viral infections. Through the production of interleukin-13, ILC2 contribute to the fight against worm infections. Furthermore, ILC2 also contribute significantly to the pathogenesis of allergic inflammation of the respiratory tract and atopic eczema. Analogous to Th2 cells, ILC2 cells can also dampen excessive inflammatory reactions.

Group 3 ILCs

These ILCs express the cytokines IL22 and IL17. This group includes the so-called "lymphoid tissue inducer" (LTi) cells, which are necessary for the formation of secondary lymphatic systems such as lymph nodes or Peyer's plaques during embryogenesis.

A second cell type in this group are the ILC3 cells, which are mainly found in the intestinal tract. These are of central importance for the immunological balance of the intestinal microbiome. At the intestinal mucosa, ILC3s act on the immune situation of the intestinal mucosa and the intestinal microbiome by producing antimicrobial peptides. ILC3 cells are one of the first targets in acute GvHD (Ziemer M et al. 2020).

The prototype of the ILC is the natural killer cell (NK cell), which has been known for many years and is important for the elimination of virus-infected and malignant cells.

In addition, "lymphoid tissue inducer" (LTi) cells have been described, which are responsible for the formation of lymph nodes during embryogenesis.

Pedigree: ILC probably all originate from a common progenitor cell in the bone marrow, the "common lymphoid progenitor" (CLP). B cells and T cells also develop from this common progenitor, which in turn is derived directly from the haematopoietic stem cell (hSC) in the bone marrow. The different subgroups of the ILC develop from this precursor depending on group-specific transcription factors. They exert their function mainly through the secretion of cytokines, whereby the cytokine profile of the ILC subgroups reflects the profile of the different T-helper cell subtypes.

1. Bonefeld CM et al. (2016) The role of innate lymphoid cells in healthy and inflamed skin. Immunol Lett doi: 10.1016/j.imlet.2016.01.005.
2. Fan X et al. (2016) Hallmarks of Tissue-Resident Lymphocytes. Cell 164:1198-1211.
3. Gladiator A et al. (2013) Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J Immunol 190:521-525.
4. Li Z et al. (2016) Epidermal Notch1 recruits RORγ(+) group 3 innate lymphoid cells to orchestrate normal skin repair. Nat Commun 7:11394.
5. Rak GD et al. (2016) IL-33-Dependent Group 2 Innate Lymphoid Cells Promote Cutaneous Wound Healing. J Invest Dermatol 136:487-496.
6. Poel van de S. et al. (2013) Innate lymphoid cells: new players in the immunological orchestra. Allergo J 22: 462-463
7. Skabytska Y et al. (2016) How the innate immune system trains immunity: lessons from studying atopic dermatitis and cutaneous bacteria. J Dtsch Dermatol Ges 14:153-156.

8. Ziemer M et al. (2020) Skin manifestations of acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. Dermatology 71:557-568.