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

CD4+ senescent T cell percentages are significantly higher in asthma patients than in healthy controls, while CD8+ Tsen percentages do not show a significant increase.

• Senescent T cells were identified by the CD57+CD28- phenotype.
• The increase in Tsen percentages was specific to the CD4+ subset.
• CD8+ Tsens did not appear to increase in asthma patients compared to healthy controls.
• Both blood and sputum samples from asthma patients were analyzed.

CD4+ Tsen percentages in blood and sputum are positively correlated with fractional exhaled nitric oxide (FeNO) values, eosinophil abundance, and Th2 cell abundance in the blood.

• Positive correlations were observed between CD4+ Tsens and FeNO, a marker of type 2 airway inflammation.
• CD4+ Tsen percentages also positively correlated with eosinophil abundance.
• CD4+ Tsen percentages positively correlated with Th2 cell abundance in blood.
• Correlations were assessed in both blood and sputum compartments.

In a house dust mite (HDM)-induced mouse model of asthma, CD4+ Tsen percentages were elevated in the lungs.

• The HDM-induced mouse model was used to recreate clinical manifestations of asthma.
• Elevated CD4+ Tsen percentages were detected in lung tissue of HDM-exposed mice.
• This finding mirrored the increase in CD4+ Tsens observed in human asthma patients.

IL-4 neutralization reduced CD4+ Tsen percentages and inhibited p38 MAPK activation in HDM-exposed mice.

• IL-4 antibodies were administered as a therapeutic intervention in the HDM mouse model.
• Dexamethasone was also administered as a comparator therapeutic intervention.
• IL-4 neutralization reduced CD4+ Tsen percentages in the lungs of asthma mice.
• The reduction in CD4+ Tsens was accompanied by inhibition of p38 mitogen-activated protein kinase (MAPK) activation, implicating this pathway in IL-4-driven T-cell senescence.

Adoptive transfer of CD4+ Tsens did not induce spontaneous asthma in PBS-treated mice but exacerbated type 2 inflammation in HDM-treated mice.

• CD4+ Tsens were adoptively transferred into both PBS-treated (healthy) and HDM-treated (asthmatic) mice.
• No spontaneous asthma phenotype was observed in PBS-treated mice receiving CD4+ Tsens.
• In HDM-treated mice, adoptive transfer of CD4+ Tsens worsened type 2 inflammatory responses.
• These results suggest CD4+ Tsens amplify rather than initiate type 2 inflammation in the context of asthma.