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Comparative Study
. 2007 Dec;120(6):1441-8.
doi: 10.1016/j.jaci.2007.08.012. Epub 2007 Oct 24.

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

Yael Gernez  1 , Rabindra Tirouvanziam, Khoa D Nguyen, Leonard A Herzenberg, Alan M Krensky, Kari C Nadeau
Affiliations
Comparative Study

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

Yael Gernez et al. J Allergy Clin Immunol. 2007 Dec.

Abstract

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(H)2 cytokines IL-4 and IL-10 and the T(H)1 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.

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Conflict of interest statement

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

Figures

FIG 1
FIG 1
Single-cell quantification of intracellular phospho-STATs in live CD4+CD161+ blood T cells by means of flow cytometry. A, The live fraction of CD4+CD161+ T cells is precisely identified based on low staining with the fixable Live/Dead probe (upper panel), followed by a scatter gate (lower panel). B, In the absence of any stimulation, live purified CD4+CD161+ T cells show distinct expression of phospho-STATs compared with background control values. Representative data from 1 allergic asthmatic patient and 1 healthy control subject are shown, as indicated.
FIG 2
FIG 2
Phospho-STAT6 and phospho-STAT1 levels, but not phospho- STAT5 levels, are increased in CD4+CD161+ blood T cells from asthmatic patients and distinguish allergic from nonallergic patients. A, B, and C, Box plots (with median line in box delimited by 25th and 75th quantiles ± 1.5 × interquartile range, as shown by whiskers) of phospho-STAT6, phospho-STAT1, and phospho-STAT5 values in allergic asthmatic patients (AA), nonallergic asthmatic patients (NA), and healthy control subjects (HC).
FIG. 3
FIG. 3
OCS treatment in allergic asthmatic patients decreases plasma IL-4 and IgE levels and phospho-STAT6 levels in blood CD4+CD161+ T cells. A, B, and C, Box plots of plasma IL-4 levels, plasma IgE levels (shown as Log10 caused by lognormal distribution), and phospho-STAT6 levels in blood CD4+CD161+ T cells, respectively, for allergic asthmatic patients not taking (AA) or taking OCSs (OCS). In Fig 3, C, 2 patients (square boxes) were prescribed OCSs but did not take them. Two individuals yielded pre- and post-OCS data (solid circles with matching lines).
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