Type 2 inflammation accelerates CD4T-cell senescence in asthma.

Abstract

Asthma is a complex and chronic inflammatory airway disease associated with the abnormal activation of immune cells. T-cell senescence is linked to immune dysfunction and persistent inflammation, but the relationship between asthma and T-cell senescence remains unexplored. This study reveals significantly higher percentages of cluster of differentiation 4-positive (CD4) senescent T cells (Tsens) in asthma patients than in healthy controls, while CD8Tsen percentages do not appear to increase. CD4Tsen percentages in both the blood and sputum are positively correlated with fractional exhaled nitric oxide (FeNO) values, eosinophil abundance, and T helper type 2 (Th2) cell abundance in the blood. The clinical manifestations of asthma were recreated in a house dust mite (HDM)-induced mouse model. In HDM-exposed mice, CD4Tsen percentages were also elevated in the lungs. To counteract T-cell senescence, therapeutic interventions, including interleukin-4 (IL-4) antibodies and dexamethasone, were administered to the mice. IL-4 neutralization reduced CD4Tsen percentages and inhibited p38 mitogen-activated protein kinase (MAPK) activation. Adoptive transfer of CD4Tsens did not induce spontaneous asthma in phosphate-buffered saline (PBS)-treated mice but exacerbated type 2 inflammation in HDM-treated mice. Our study revealed a significant increase in CD4Tsen (CD57CD28) abundance in asthma patients and suggested that type 2 inflammation drives CD4T-cell senescence in asthma. Furthermore, adoptive transfer of CD4Tsens appears to exacerbate type 2 inflammation.