Altered phosphorylated signal transducer and activator of transcription profile of CD4⁺CD161⁺ T cells in asthma: Modulation by allergic status and oral corticosteroids

Background: Asthma is a complex immunologic disorder linked to altered cytokine signaling. Objective: We tested whether asthmatic patients showed any change in cytokine-dependent signal transducer and activator of transcription (STAT) levels, focusing on the central/effector-memory CD4⁺CD161⁺ subset, which represents 15% to 25% of circulating T cells. Methods: We quantified intracellular levels of active phosphorylated STAT (phospho-STAT) 1, 3, 5, and 6 by means of flow cytometry, without any activation or expansion. Results: Baseline phospho-STAT1 and phospho-STAT6 levels were increased in CD4⁺CD161⁺ T cells from asthmatic patients compared with those from healthy control subjects (by 10- and 8-fold, respectively). This asthma-associated alteration was both subset specific because no change was seen in CD4⁺CD161^-CD25⁺ (regulatory T cells) and CD4⁺CD161^-CD25^- subsets and isoform specific because phospho-STAT5 and phospho-STAT3 levels were unchanged. Among asthmatic patients, phospho-STAT1 and phospho-STAT6 levels correlated negatively with each other, suggesting antagonistic regulation. Oral corticosteroid (OCS) treatment significantly decreased phospho-STAT6 and IL-4 levels but not phospho-STAT1 levels. Disease parameters showing significant correlations with phospho-STAT1, phospho-STAT6, or both included age at onset, plasma IgE levels, and levels of the T_H2 cytokines IL-4 and IL-10 and the T_H1 cytokine IL-2. Overall, combined phospho-STAT1 and phospho-STAT6 measurements showed excellent predictive value for identifying (1) asthmatic patients versus healthy control subjects, (2) allergic versus nonallergic asthmatic patients, and (3) asthmatic patients taking versus those not taking OCSs. Conclusion: Baseline changes in phospho-STAT1 and phospho-STAT6 levels in blood CD4⁺CD161⁺ T cells identify asthmatic patients and mirror their allergic status and response to OCSs. Clinical implications: These results confirm the pathologic importance of activated STAT1 and STAT6 in asthma and suggest their potential use as clinical biomarkers.