Single-cell analysis reveals innate lymphoid cell lineage infidelity in atopic dermatitis

Abstract

events were demonstrated in ILCs from skin explant cultures and in vitro expanded ILCs from the peripheral blood. Conclusion: These findings support the concept that instead of being a stable entity with well-defined components, the skin immune system consists of a network of highly flexible cellular players that are capable of adjusting their function to the needs and challenges of the environment. (J Allergy Clin Immunol 2021;nnn:nnn-nnn.)

Heterogeneity of type 2 innate lymphoid cells

“…Instead, inflammation was mediated by IL-23-driven conversion of homeostatic skin ILC2s into a pathogenic ILC3-like state (Box 1 ). These data are supported by a recent single-cell RNA sequencing study of human psoriatic skin, which revealed a spectrum of ILCs with mixed features of ILC2s and ILC3s 92 . By contrast, in humans, psoriasis is associated not only with enrichment of dermal IL-17 + IL-22 + ILC3s 25 but also with an increase in the number of circulating ILC3s 93 and skin-homing RORγt + CD117 + ILC2s 25 , which suggests that progenitors of ILC3s migrate to psoriatic skin and that mature ILC3s are extruded from psoriatic skin.…”

Cytokine-Mediated Crosstalk Between Keratinocytes and T Cells in Atopic Dermatitis

“…One of the classical features of AD is a strong type 2 immune response that leads to skin barrier dysfunction, such as inhibition of epidermal differentiation and increased skin permeability ( 3 ). Inflammatory cell infiltration found in lesional AD skin is characterized by the presence of type 2 innate lymphoid cells (ILC2) and various T cell subpopulations producing cytokines driving a T helper (Th) type 2-predominant inflammation ( 7 , 8 ). Keratinocytes, the predominant cell type of the epidermis, are also key players in the AD pro-inflammatory environment ( 9 ).…”

Cutaneous Type 2 Innate Lymphoid Cells Come in Distinct Flavors

“…AD lesional skin is characterized by a defective skin barrier and a type-2‒dominated local immune response ( Weidinger et al., 2018 ). AD skin lesions demonstrate increased expression of type-2‒promoting epithelial cytokines IL-33, TSLP, and IL-25 and increased numbers of type 2 innate lymphoid cells (ILC2s) that express high levels of receptors for these cytokines ( Alkon et al., 2021 ; Kim et al., 2013 ; Salimi et al., 2013 ; Savinko et al., 2012 ; Soumelis et al., 2002 ). IL-33, TSLP, and IL-25, alone or in combination, promote type 2 cytokine production by ILC2s in vitro ( Salimi et al., 2013 ).…”

“…(2021) is whether the two distinct populations of cutaneous ILC2s exist in normal mouse skin or in other mouse models of skin inflammation and importantly in normal or inflamed human skin. Single-cell RNAseq analysis of healthy and AD lesional skin shows that skin ILCs are a heterogeneous population, including ILC1s, ILC2s, ILC3s, and ILC precursors, with ILC2s being predominant ( Alkon et al., 2021 ). Furthermore, ILC2s in normal human skin were found to be a homogenous population that expresses type 2 cytokines IL-13 and IL-4 and the transcription factor GATA3, whereas ILC2s present in AD lesional skin were found to be heterogeneous and expressed type 2 as well as type 17 cytokines and the transcription factors that drive these cytokines, including GATA3, AHR, and RORC ( Alkon et al., 2021 ).…”

“…Single-cell RNAseq analysis of healthy and AD lesional skin shows that skin ILCs are a heterogeneous population, including ILC1s, ILC2s, ILC3s, and ILC precursors, with ILC2s being predominant ( Alkon et al., 2021 ). Furthermore, ILC2s in normal human skin were found to be a homogenous population that expresses type 2 cytokines IL-13 and IL-4 and the transcription factor GATA3, whereas ILC2s present in AD lesional skin were found to be heterogeneous and expressed type 2 as well as type 17 cytokines and the transcription factors that drive these cytokines, including GATA3, AHR, and RORC ( Alkon et al., 2021 ). Similar ILC2 plasticity has been observed in a mouse model of psoriasis induced by recombinant IL-23 injection ( Bielecki et al., 2021 ).…”