Correlation between peripheral blood T-cell profiles and airway inflammation in atopic asthma

doi:10.1016/j.jaci.2006.05.005

Journal of Allergy and Clinical Immunology

Volume 118, Issue 3, September 2006, Pages 622-626

https://doi.org/10.1016/j.jaci.2006.05.005 Get rights and content

Background

Recent studies suggest that T_H1/T_H2 and T_C1/T_C2 cell imbalances are implicated in asthma pathogenesis. However, the relationship of T-cell profiles to airway inflammation has not been understood.

Objective

The purpose of this study was to clarify the correlation between peripheral blood T-cell profiles and airway inflammatory parameters.

Methods

Subjects included 21 patients with atopic asthma and 20 healthy control subjects. After stimulation with phorbol 12-myristate 13-acetate and ionomycin, flow cytometry was used to analyze intracellular cytokine staining for IFN-γ and IL-4 in peripheral blood CD4⁺ and CD8⁺ T cells. Airway inflammation was assessed by using exhaled nitric oxide analysis and induced sputum eosinophil counts.

Results

There were a significantly increased proportion of IL-4–producing CD4⁺ T cells (median, 2.7% [interquartile range, 2.4% to 3.3%] vs 1.8% [interquartile range, 1.3% to 2.7%]) and a lower ratio of IFN-γ–producing/IL-4–producing CD4⁺ T cells (7.3% [interquartile range, 5.8% to 9.5%] vs 10.0% [interquartile range, 8.8% to 13.2%]) in asthmatic patients compared with in healthy subjects (P < .01) but no increase or decrease in the proportion of IFN-γ–producing CD4⁺ T cells. No significant difference was found in the proportion of IFN-γ– or IL-4–producing CD8⁺ T cells between the 2 groups. The proportion of IL-4–producing CD4⁺ T cells was significantly correlated with exhaled nitric oxide (r = 0.48, P < .05) and induced sputum eosinophil counts (r = 0.50, P < .05).

Conclusion

These findings indicate a correlation between peripheral blood T_H2 cytokine production and markers of airway inflammation.

Clinical implications

There is an association between immune function and clinical indicators in asthma.

Section snippets

Subjects

Twenty-one patients with atopic asthma and 20 nonatopic healthy control subjects were enrolled in the study (Table I). These consecutive patients with atopic asthma first visited Fujinomiya City General Hospital from December 2003 through November 2004, satisfied the American Thoracic Society criteria,¹⁶ and had asthmatic symptoms within 1 week before the first visit. The severity of asthma was intermittent or mild persistent according to the classification of the Global Initiative for Asthma.¹⁷

Peripheral blood T-cell profiles: Comparison between atopic asthmatic and healthy subjects

Under unstimulated conditions, we could find no cytokine-expressing cells in the CD4⁺ or CD8⁺ T-cell population of peripheral blood cells in patients or healthy control subjects.

In response to PMA/ionomycin, no significant difference was found in the proportion of IFN-γ–producing CD4⁺ T cells between patients with atopic asthma and healthy control subjects (Fig 1, upper left panel). However, the percentage of IL-4–producing CD4⁺ T cells was significantly higher in the patients (Fig 1, upper

Discussion

In this study we found a significantly higher percentage of IL-4–producing CD4⁺ T cells together with a significantly lower ratio of IFN-γ–producing/IL-4–producing CD4⁺ T cells in peripheral blood after PMA/ionomycin stimulation in patients with atopic asthma compared with healthy control subjects. However, there was no difference in the percentage of IFN-γ–producing CD4⁺ T cells between the 2 groups. Our study provides direct support for the T_H2 hypothesis that an increased production of T_H2

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When simulation running with hyper-response ends, there are more DCs, IL23 and TH17 cells in zone 2. Since fewer DCs under bacterial infection are activated to win infection, they convene more DCs producing high response, and enter zone 2 to induce more IL23 cells (Shirai et al., 2006; Kallinich et al., 2007), whereas IL-23 can induce TH17 and more TH17 factors can cause severe asthma. This is consistent with the clinical data (see Figs. 3 and 4 in Zhao et al., 2010).
TH17 is a subset of CD4+T cells. Comparing to common asthma patients, there are more TH17 cells in the respiratory systems of the patients with severe asthma. TH17 cells are mainly adjusted by IL23 to produce IL17A and IL17F, which act on the epithelial cells and cause severe asthma. However, the TH17 function in severe asthma as a driving mechanism of neutrophilic inflammation is not yet fully understood and deserves further study. However, it is very difficult to describe the interactions between TH17 and other cells using mathematics equations due to the high complexity of immunity system. In order to explore the TH17 function in severe asthma, we used BIS (Basic Immune Simulator) platform to simulate TH17 models, and compared DC (Dendritic Cell) models with TH17 models. We studied the interaction between innate immune and adaptive immune cells, which was resulted from TH17 cells. The simulation results for the TH17 models are consistent with clinical data, which suggests that DC–IL23–TH17 axis might be the path of causing severe asthma. Our simulation studies support a role for TH17 in severe asthma, and hence it could be taken as a new target candidate for clinical treatment of severe asthma.
Correlation between peripheral blood T-cell profiles and clinical and inflammatory parameters in stable COPD
2010, Allergology International
Recent studies suggest that Tcl/Tc2 imbalances are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The purpose of this study was to clarify the relationship between peripheral blood T-cell profiles and pulmonary function or inflammatory parameters.
Thirty-one patients with stable COPD (median age 70 years, 30 males, 15 current smokers and 16 ex-smokers) and 30 healthy control subjects were enrolled in this study. The subjects underwent blood tests, exhaled nitric oxide (eNO) measurement, pulmonary function tests, and sputum induction. Tc1/Tc2 and Th1/Th2 were determined by analyzing intracellular cytokine staining for IFN-γ and IL-4 in peripheral blood CD8 + and CD4 + T cells using flow cytometry after stimulation with phorbol 12-myristate 13-acetate and ionomycin.
There was a significantly increased proportion of IFN-γ-producing and IL-4-producing CD8 + T cells in patients with COPD compared with control subjects (median [IQR] 73.6% [63.9%-80.7%] vs 62.0% [45.6%-73.8%], p = 0.004; and 2.6% [1.1%-6.9%] vs 1.1% [0.6%-2.2%], p = 0.002, respectively). In addition, the proportion of IFN-γ-producing CD4 + T cells was significantly higher in patients with COPD compared with control subjects (25.7% [21.2%-38.0%] vs 22.8% [15.6%-29.2%], p = 0.027). The proportion of IFN-γ-producing CD8 + T cells was correlated negatively with single-breath carbon monoxide transfer coefficient (Kco) (ρ = − 0.45, p = 0.033) and positively with eNO (ρ = 0.50, p = 0.012). The proportion of IL-4-producing CD8 + T cells was positively correlated with body mass index (ρ = 0.42, p = 0.023) and Kco (ρ = 0.47, p = 0.026).
It is suggested that Tc1 cells have a detrimental role and that Tc2 cells have a protective role in disease progression.
CD8+ T cells in asthma: Friend or foe?
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While it is well established that CD4⁺ T lymphocytes play a crucial role in the initiation, progression and persistence of asthma, the role of CD8⁺ T cells is less understood. CD8⁺ T cells form functionally similar subsets which exhibit similar cytokine profiles as Th1 and Th2 cells, known as Tc1 and Tc2. Evidence from animal studies suggest that CD8⁺ T cells are capable of regulating IgE production through the induction of IL-12 and IL-18 production in dendritic cells, and that CD8⁺ T cells may act to moderate Th2 polarisation within the localised lymph nodes during allergic sensitisation. Such findings have led to the suggestion that Th1 polarising, CD8⁺ T cell-inducing vaccines would inhibit the development of airway hyperresponsiveness (AHR) and Th2 cell infiltration. Despite these positive findings, the role of CD8⁺ T cells within the lung remains poorly understood. While CD8⁺ T cells, particularly those expressing the Tc1 phenotype, are capable of moderating inflammation and suppressing AHR, it has been postulated that Tc2 CD8⁺ T cells predominate within established asthma and may act to amplify the inappropriate immune response which defines the condition. Within the clinic, the association between CD8⁺ T cells and asthma is almost universally defined as injurious, further suggesting a prejudicial role for these cells within the established disease. CD8⁺ T cells may be a valuable potential target for therapeutic intervention, either by potentiating their regulatory effects prior to the development of sensitisation, or through suppressing their pro-inflammatory properties within established atopy.
Altered phosphorylated signal transducer and activator of transcription profile of CD4+CD161+ T cells in asthma: Modulation by allergic status and oral corticosteroids
2007, Journal of Allergy and Clinical Immunology
Asthma is a complex immunologic disorder linked to altered cytokine signaling.
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.
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.
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.
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.
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Citation Excerpt :
An ongoing debate surrounds the relevance of T cells in the periphery to immune events occurring at sites of allergic inflammation (eg, respiratory tract and skin). Recently, increased circulating IL-4–producing CD4+ T cells have been correlated with markers of airway inflammation.92 However, few studies have examined changes in circulating allergen-specific T cells that are associated with asthma exacerbations.
The allergic response in human beings is engineered by CD4⁺ T lymphocytes, which secrete T_H2 cytokines in response to activation by allergen-derived peptides. Although T_H2 cells have been well characterized, defining the properties of allergen-specific T cells has proved challenging in human beings because of their low frequency within the T-cell repertoire. However, recent studies have provided insight into the molecular signature of long-lived human memory T_H2 cells, which are allergen-specific. T-cell responses directed against allergens develop in early life and are heavily influenced by the type and dose of allergen, and possibly coexposure to microbial products. These responses are susceptible to suppression by regulatory T cells. This article highlights recent advances in the characterization of allergen-specific memory T_H2 cells and discusses the heterogeneous nature of regulatory T cells and possible mechanisms of action. The relevance of T-cell epitope mapping studies to understanding the unique nature of T-cell responses to different allergens, as well as to peptide vaccine development, is reviewed. Experimental techniques and approaches for analyzing allergen-specific T cells and identifying novel T-cell epitopes are described that may lead to new T-cell–based therapies.
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: Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

View full text

Mechanisms of asthma and allergic inflammationCorrelation between peripheral blood T-cell profiles and airway inflammation in atopic asthma

Background

Objective

Methods

Results

Conclusion

Clinical implications

Section snippets

Subjects

Peripheral blood T-cell profiles: Comparison between atopic asthmatic and healthy subjects

Discussion

Immunol Methods

J Allergy Clin Immunology

J Allergy Clin Immunol

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

Immunol Today

Immunol Today

Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma

N Engl J Med

Allergy and allergic diseases. First of two parts

N Engl J Med

Asthma

N Engl J Med

Th1/Th2 profile in peripheral blood in atopic cough and atopic asthma

Clin Exp Allergy

Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-γ, IL-4, IL-10 and IL-13) in patients with allergic asthma

Clin Exp Immunol

Mechanisms of asthma and allergic inflammation
Correlation between peripheral blood T-cell profiles and airway inflammation in atopic asthma