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Differential regulation of PD-1 and its ligands in allergic asthma
K Bratke1, L Fritz1, F Nokodian1
1Department of Pneumology, University of Rostock, Rostock, Germany.
Background:
Targeting PD-1/PD-1 ligand signalling is an established treatment option for cancer. The role of these molecules in allergic asthma has been investigated in several mouse studies yielding conflicting results. However, human studies investigating the expression and regulation of PD-1 and its ligands in allergic inflammation are lacking.
Objective:
To analyse the expression and regulation of PD-1 and its ligands in human allergic asthma.
Methods:
The well-established human asthma model of segmental allergen challenge (SAC) was used to analyse the regulation of PD-1 and its ligands PD-L1 and PD-L2 on T lymphocytes and dendritic cells by flow cytometry. The impact of immunoglobulin E (IgE)-mediated signalling on PD-L1 expression was analysed on isolated plasmacytoid dendritic cells (pDCs).
Results:
PD-1 expression by blood CD4+ T cells was negatively associated with total and specific (against the allergen used for provocation) IgE serum concentrations. Twenty-four hours after SAC, a small decrease in endobronchial PD-1+ CD4+ T cells was accompanied by an increase in PD-L1 expression on endobronchial myeloid dendritic cells (mDCs) and pDCs. The PD-L1 up-regulation on pDCs was not induced by IgE-mediated mechanisms. In contrast, PD-L2 was only detected on endobronchial mDCs and was significantly down-regulated 24 hours after SAC.
Conclusion And Clinical Relevance:
This study shows, for the first time, an association of a low PD-1 expression by circulating CD4+ T cells with high total and specific (against the allergen used for provocation) IgE concentrations in allergic asthma. In addition, we demonstrate a differential regulation of PD-1 ligands on endobronchial DCs after allergen challenge which may favour Th2 inflammation. Therefore, modulating PD-1 ligand-mediated pathways might be a promising target in allergic asthma.
Insights
In allergic asthma, lower PD-1 expression on T cells correlates with higher IgE levels. Allergen challenge alters PD-1 ligand expression on dendritic cells, potentially promoting inflammation.
Area of Science:
- Immunology
- Allergy Research
- Cancer Immunotherapy
Background:
- Programmed cell death protein 1 (PD-1) and its ligands are key regulators of immune responses.
- While targeted in cancer therapy, their role in allergic asthma remains unclear, with conflicting data from animal studies.
- Human studies on PD-1 and ligand expression in allergic inflammation are scarce.
Purpose of the Study:
- To investigate the expression and regulation of PD-1 and its ligands (PD-L1, PD-L2) in human allergic asthma.
- To analyze these molecules in the context of allergen challenge and IgE levels.
Main Methods:
- Utilized a human asthma model involving segmental allergen challenge (SAC).
- Analyzed PD-1, PD-L1, and PD-L2 expression on T lymphocytes and dendritic cells via flow cytometry.
- Assessed the impact of immunoglobulin E (IgE) on PD-L1 expression in plasmacytoid dendritic cells (pDCs).
Main Results:
- Lower PD-1 expression on circulating CD4+ T cells was associated with higher total and specific IgE concentrations.
- Following SAC, endobronchial PD-1+ CD4+ T cells decreased, while PD-L1 expression increased on myeloid dendritic cells (mDCs) and pDCs.
- PD-L2 expression on mDCs decreased post-allergen challenge; IgE did not drive PD-L1 upregulation on pDCs.
Conclusions:
- This study reveals a novel association between reduced PD-1 on T cells and elevated IgE in allergic asthma.
- Demonstrated differential regulation of PD-1 ligands on dendritic cells after allergen challenge, potentially exacerbating Th2 inflammation.
- Targeting PD-1 ligand pathways presents a potential therapeutic strategy for allergic asthma.
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