NOD2 Agonism Counter-Regulates Human Type 2 T Cell Functions in Peripheral Blood Mononuclear Cell Cultures:...

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• Atopic dermatitis (AD) involves T cell immunopathology linked to disease severity.
• Skin *Staphylococcus aureus* (*S. aureus*) and host-pathogen interactions drive chronic T helper 2 (Th2) inflammation in AD, but are poorly understood.
• Th2-type cells, cytokines, and chemokines are associated with AD pathogenesis.

Purpose of the Study:

• To investigate the effects of *S. aureus*-derived molecules and skin alarmins on human peripheral blood mononuclear cells.
• To analyze Th2-type cells, cytokines, and chemokines relevant to AD.
• To identify potential therapeutic targets for AD.

Main Methods:

• Analysis of chemokine biomarkers in adult AD patients versus healthy controls ex vivo.
• In vitro modeling using healthy blood mononuclear cells exposed to the alarmin TSLP and *S. aureus* superantigen SEB.
• Assessment of T cell activation, cytokine/chemokine secretion, and signaling pathways (e.g., pSTAT3, IL-6) following NOD2 agonism.

Main Results:

• Six Th2-related chemokine biomarkers were elevated in AD patients' blood, with TARC/CCL17, LDH, and PDGF-AA/AB correlating with disease severity.
• TSLP and SEB exposure reproduced AD-associated biomarkers and type 2 T cell functions, including IL-13, IL-5, and TARC secretion, and activated memory T cells.
• NOD2 agonism inhibited IL-13 secretion and Th2/Tc2 cell activation, while increasing pSTAT3 and IL-6, indicative of Th17 responses.

Conclusions:

• NOD2 acts as a potential regulator of type 2 immune responses in humans.
• NOD2 functions as an endogenous inhibitor of pathogenic IL-13.
• Targeting NOD2 may offer novel therapeutic avenues for atopic dermatitis.