NFATc1 in CD4+ T cells and CD11c+ dendritic cells drives TH2-mediated eosinophilic inflammation in allergic asthma

Background

Asthma, a chronic lung disease, is a significant public health problem worldwide. It is marked by increased T_H2 response resulting in eosinophil accumulation. The pathophysiology of asthma involves various cell types, including epithelial cells, dendritic cells (DCs), innate lymphoid cells, B cells, and effector cells. Nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a critical transcription factor for immune regulation, is known for its role in T cells and, more recently, in myeloid cells. However, the specific contributions of NFATc1 in T cells and DCs in the context of asthma are not well understood.

Objective

We explored NFATc1’s role in T cells and DCs in modulating T_H2 immune responses within the pathophysiology of allergic asthma.

Methods

We induced asthma in mice lacking Nfatc1 in CD4⁺ T cells or CD11c⁺ DCs using house dust mite, thereby enabling investigation into NFATc1’s role in both cell types in experimental allergic asthma. Additionally, we examined NFATc1 expression in these cell types and its correlation with blood eosinophil levels in an adult asthma cohort.

Results

In a house dust mite–induced asthma model, we found that Nfatc1 deficiency either in CD4⁺ T cells or CD11c⁺ DCs resulted in reduced T_H2-driven eosinophilic inflammation, IgE levels, and mast cell presence in the lung of asthmatic mice. Nfatc1’s absence in CD4⁺ T cells directly hampered T_H2 cell polarization and functionality, whereas in CD11c⁺ DCs, it affected DC differentiation and maturation, thereby weakening T-cell priming, proliferation, and subsequent T_H2 differentiation. Correspondingly, translational research indicated significant correlations between CD4⁺NFATc1⁺ and CD11c⁺NFATc1⁺ cell populations and eosinophil levels in asthmatic patients, but not in healthy controls.

Conclusion

NFATc1 in T cells and DCs modulates T_H2-mediated eosinophilic inflammation in allergic asthma, thus offering insight into asthma pathogenesis and identifying NFATc1 as a potential target for therapeutic intervention.