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Science
16 March 2025

New Study Identifies Distinct Subsets Of Pathogenic Th2 Cells

Research uncovers key factors driving allergic asthma and highlights epigenetic influences.

Allergic asthma affects over 300 million people worldwide, contributing significantly to the global burden of chronic diseases. A recent study from researchers at the Medical University of Vienna sheds light on the cells involved in this condition, particularly focusing on pathogenic T helper type 2 (pTh2) cells—critical players generating inflammatory responses. Using advanced single-cell RNA sequencing, the study identifies two distinct subsets of pTh2 cells and emphasizes the role of histone deacetylase 1 (HDAC1) in their function and differentiation.

Allergic asthma is orchestrated by type 2 cytokine-producing cells like pTh2, which drive airway inflammation through the release of pro-inflammatory cytokines such as Interleukin-4 (IL-4) and Interleukin-5 (IL-5). The new research indicates, "Our analyses indicate two distinct highly proinflammatory subsets of lung pTh2 cells." These cells are instrumental in fostering allergic reactions, yet many details surrounding their maturation and specific functioning mechanisms remain poorly understood.

The researchers undertook their investigation by studying mice exposed to the common indoor allergen, house dust mites. This involved isolting lung CD4+ T cells and performing low-input single-cell RNA sequencing to capture the cellular dynamics involved. Their findings provide insights not only on pTh2 cell signatures but also on the regulatory capacity of HDAC1.

HDAC1 has garnered attention due to its role as an epigenetic modifier—controlling gene expression without altering DNA sequences. Its function appears complex, as the absence of HDAC1 potentiated the severity of allergic responses, particularly enhancing the pathogenicity of pTh2 subsets. The team observed, "We have generated insights about the pathogenic features of pTh2 cells and their significance in allergic diseases." This suggests potential therapeutic targets by modulating HDAC1, which has previously been linked to the regulation of immune responses.

An assessment of the two identified pTh2 cell subsets revealed they express various genes associated with inflammation and tissue repair, positioning them as potential targets for new asthma treatments. Flow cytometry analyses pinpointed specific surface markers to distinguish between pTh2 populations and regulatory T cells (Treg/Th2), stressing the importance of identifying reliable markers to delineate these subsets during allergic responses.

Complementing these cellular analyses, the researchers highlighted the roles of thymic stromal lymphopoietin (TSLP) and members of the tumor necrosis factor receptor superfamily as drivers for pTh2 generation. This finding is pivotal, considering how allergic inflammation is often triggered by interactions between various immune signaling pathways.

The study concludes by underscoring HDAC1’s importance as not just another regulator, but as a gatekeeper for maintaining the balance of immune responses, particularly during defined pathogenic contexts. This scholarly work establishes both the presence of heterogeneity among pTh2 cell subsets and the molecular underpinnings anchoring their differentiation.

Future inquiries should focus on utilizing the findings to develop targeted therapies aimed at manipulating HDAC1 or the pathways involved, potentially leading to innovative treatments for allergic conditions including asthma, allergic rhinitis, and atopic dermatitis.