Type 2 inflammation accelerates CD4+ T-cell senescence in asthma

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 CD8⁺ Tsen percentages do not appear to increase. CD4⁺ Tsen 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, CD4⁺ Tsen 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 CD4⁺ Tsen percentages and inhibited p38 mitogen-activated protein kinase (MAPK) activation. Adoptive transfer of CD4⁺ Tsens 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 CD4⁺ Tsen (CD57⁺CD28^-) abundance in asthma patients and suggested that type 2 inflammation drives CD4⁺ T-cell senescence in asthma. Furthermore, adoptive transfer of CD4⁺ Tsens appears to exacerbate type 2 inflammation.