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Published on: April 8, 2016
IL-18 skews the invariant NKT-cell population via autoreactive activation in atopic eczema
Sara M Lind1, Carlotta Kuylenstierna, Markus Moll
1Clinical Allergy Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
Abstract:
Atopic eczema (AE) is a chronic relapsing inflammatory skin disease where the commensal yeast Malassezia can act as a microbial trigger factor. Malassezia activates human DC to produce IL-18, an innate cytokine that is elevated in serum of AE patients; however, the precise role of IL-18 in human AE etiology is unknown. Herein, we investigated the effect of IL-18 on the human invariant NKT (iNKT) cell compartment in AE. We found that IL-18 was a potent activator of human iNKT-cells and promoted a pro-inflammatory CD1d-dependent response, even in the absence of exogenous ligands. Chronic activation via IL-18 on the other hand was inhibitory and skewed the iNKT-cell pool by selectively suppressing CD4(+) iNKT-cells. This was mimicked in AE patients where the proportion of CD4(+) iNKT-cells was reduced in peripheral blood and coincided with elevated plasma levels of IL-18. Furthermore, a reduced CD4(+) iNKT-cell pool was associated with elevated IgE levels in plasma, and the plasma levels of IL-18 correlated with both total IgE and disease severity in the AE patients. Based on these findings, we propose that IL-18-mediated activation and subsequent dysregulation of the CD1d-restricted iNKT-cells plays a role in the pathogenesis of human AE.
Insights
Interleukin-18 (IL-18) activates invariant natural killer T (iNKT) cells in atopic eczema (AE). Chronic IL-18 exposure suppresses CD4(+) iNKT cells, correlating with AE severity and IgE levels.
Area of Science:
- Immunology
- Dermatology
- Microbiology
Background:
- Atopic eczema (AE) is a chronic inflammatory skin condition.
- The yeast Malassezia can trigger AE flares.
- Interleukin-18 (IL-18), an innate cytokine elevated in AE patients, is produced by dendritic cells activated by Malassezia.
Purpose of the Study:
- To investigate the role of IL-18 in the human invariant NKT (iNKT) cell compartment in AE.
- To understand how IL-18 affects iNKT cell responses in the context of AE pathogenesis.
Main Methods:
- Investigated the effect of IL-18 on human iNKT cells in vitro.
- Analyzed iNKT cell populations (CD4+ vs. CD4-) in peripheral blood of AE patients.
- Measured plasma levels of IL-18, total IgE, and correlated these with disease severity.
Main Results:
- IL-18 potently activates human iNKT cells, inducing a pro-inflammatory CD1d-dependent response.
- Chronic IL-18 exposure inhibits iNKT cells, specifically suppressing CD4+ iNKT cells.
- AE patients exhibit reduced CD4+ iNKT cell proportions, elevated IL-18 plasma levels, and a correlation between IL-18, IgE, and disease severity.
Conclusions:
- IL-18 plays a significant role in the pathogenesis of human atopic eczema.
- Dysregulation of CD1d-restricted iNKT cells by IL-18 contributes to AE development.
- Targeting IL-18 or modulating iNKT cell responses could be potential therapeutic strategies for AE.
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