Composition of Innate Lymphoid Cell Subsets in the Human Skin: Enrichment of NCR + ILC3 in Lesional Skin and Blood of Psoriasis Patients

Abstract

Innate lymphoid cells (ILCs) are increasingly appreciated as important regulators of tissue homeostasis and inflammation. However, their role in human skin remains obscure. We found that healthy peripheral blood CD117(+) ILC3, lacking the natural cytotoxicity receptor (NCR) NKp44 (NCR(-) ILC3), CD117(-)NCR(-)CRTH2(-)CD161(+) ILC1, and CRTH2(+) ILC2, express the skin-homing receptor cutaneous lymphocyte antigen (CLA). NCR(+) ILC3 were scarce in peripheral blood. Consistently, we identified in normal skin ILC2 and NCR(-) ILC3, a small proportion of CD161(+) ILC1, and hardly any NCR(+) ILC3, whereas NCR(+) ILC3 were present in cultured dermal explants. The skin ILC2 and NCR(+) ILC3 subsets produced IL-13 and IL-22, respectively, upon cytokine stimulation. Remarkably, dermal NCR(-) ILC3 converted to NCR(+) ILC3 upon culture in IL-1β plus IL-23, cytokines known to be involved in psoriatic inflammation. In line with this observation, significantly increased proportions of NCR(+) ILC3 were present in lesional skin and peripheral blood of psoriasis patients as compared with skin and blood of healthy individuals, respectively, whereas the proportions of ILC2 and CD161(+) ILC1 remained unchanged. NCR(+) ILC3 from skin and blood of psoriasis patients produced IL-22, which is regarded as a key driver of epidermal thickening, suggesting that NCR(+) ILC3 may participate in psoriasis pathology.

Innate Lymphoid Cells in Graft-Versus-Host Disease

“…For the development and function of human and mouse ILC2, the transcription factors GATA3 and RORα are essential 17. In the peripheral blood, the majority of CD127 + ILC are ILC2, additionally, group 2 ILC have been found in the healthy human lung 2, 18 and in the skin 19, 20. An updated view on ILC2 function in pulmonary and dermal inflammatory diseases is provided elsewhere 21.…”

“…NCR − ILC3 make up one of the most frequent ILC subsets in the human peripheral blood, while NCR + ILC3 are virtually absent in the circulation during homeostasis 20. Importantly, the healthy human intestine hosts dominantly NCR + ILC3, which have been shown to be essential in maintaining gut homeostasis 1.…”

“…IL‐22 could be a relatively safe target in enhancing mucosal healing, since it does not directly affect immune cell functions. However, possible adverse effects might occur, for example, due to dysregulated responses of keratinocytes in the skin 20, 37. Of note, in an earlier large‐scale clinical study investigating human gastrointestinal GVHD risk factors, Reg3α protein was identified as indicator of higher incidence for developing GVHD after allo‐HCT 38.…”

Emerging roles of innate lymphoid cells in inflammatory diseases: Clinical implications

“…12 The most prevalent ILC population in human skin is the ILC2. 3 As skin ILC2s express high levels of amphiregulin, they are implicated in tissue homeostasis and repair.…”

“…73,77 There are some differences between the studies regarding whether these skin ILC2s preferentially respond to IL-33 or TSLP. 12,73 Several ILC-modulating factors are dysregulated in AD skin. Elevated levels of IL-25, IL-33, TSLP, and PGD2 were reported, but also cell-cell interactions affect the ILC2 response ( Figure 2).…”