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Effect of memory CD4+ T cells’ signal transducer and activator of transcription (STATs) functional shift on cytokine-releasing properties in asthma

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Abstract

Background

Recent data have demonstrated that long-lived memory T cells are present in the human lung and can play significant roles in the pathogenesis of specific allergic and autoimmune diseases. However, most evidence has been obtained from mouse studies, and the potential roles of memory T cells in human allergic diseases, such as asthma, remain largely unknown.

Methods

Thirty-three asthmatics, 26 chronic obstructive pulmonary disease (COPD) patients, and 22 healthy volunteers were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated from the peripheral blood, and cell surface staining (CD4, CD45RO, CRTH2, CD62L, and CCR7) was performed for the detection of memory CD4+ T cells in blood. After stimulation with interleukin-27 (IL-27) or IL-4 for 15 min, the STAT1/STAT6 phosphorylation of memory CD4+ T cells was measured separately by flow cytometric techniques. The cytokine-releasing profiles after 6 days of culture under neutralization, TH2, TH2 + lipopolysaccharide (LPS), and TH2 + house dust mite (HDM) conditions were detected by intracellular protein (IL-5, IL-17, and interferon (IFN)-γ) staining. Correlation analyses between the profile of memory CD4+ T cells and clinical characteristics of asthma were performed.

Results

The number of circulating memory CD4+ T (CD4+ Tm) cells in asthmatics was increased compared with that in the healthy subjects (48 ± 5.7 % vs. 32 ± 4.1 %, p < 0.05). Compared with COPD and healthy subjects, the phosphorylation of signal transducer and activator of transcription 1 (STAT1-py) was impaired in asthmatics, whereas the phosphorylation of signal transducer and activator of transcription 6 (STAT6-py) was slightly enhanced. This imbalance of STAT1-py/STAT6-py was attributed to TH2 memory cells but not non-TH2 memory cells in blood. The cytokine-releasing profiles of asthmatics was unique, specifically IL-5high, IL-17high, and IFN-rlow, compared with those of COPD patients and healthy subjects. The IL-17 production levels in CD4+ Tm cells are associated with disease severity and positively correlated with medication consumption in asthma.

Conclusions

The long-lived, antigen-specific memory CD4+ T cells, rather than PBMCs or peripheral lymphocytes, might be the ideal T cell subset candidates for analyzing the endotype of asthma. Memory CD4+ T cells exhibiting a shift in STAT phosphorylation and specific cytokine-releasing profiles have the potential to facilitate the understanding of disease heterogeneity and severity, allowing the more personalized treatment of patients.

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Abbreviations

STATs:

Signal transducer and activator of transcription

CD4+Tm:

Memory CD4+ T Cells

COPD:

Chronic obstructive pulmonary disease

PBMCs:

Peripheral blood mononuclear cells

STAT1-py:

STAT1 phosphorylation

STAT6-py:

STAT6 phosphorylation

LPS:

Lipopolysaccharide

HDM:

house dust mite

ILs:

interleukins

Tem:

effector memory T cells

Tcm:

central memory T cells

Trm:

resident memory T cells

Treg:

T regulatory cell

MFIs:

Mean fluorescence intensities

GINA:

Global Initiative for Asthma

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81270078 and 81470211 to ZHC) and the “Zhengyi” Scholar Program of Fudan University (JYH6273202/002/023/014 to GS and SXC).

Author contributions

ZHC, XDW, LZ, and JP conceived and designed the study. ZHC, DDL, ZHM, XQS, HLY, GS, and SXC performed the biological experiments. YJ was responsible for the statistical analysis. ZHC and JP wrote the paper. All the authors read and approved the final manuscript.

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Authors and Affiliations

  1. Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, China

    Zhihong Chen, Jue Pan, Dandan Li, Xiaoqiong Su, Honglei Yuan & Lei Zhu

  2. Asia & Emerging Markets, iMed, AstraZeneca, Shanghai, 201203, China

    Yi Jia

  3. Research Center of Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, China

    Zhihui Min & Xiangdong Wang

  4. Department of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China

    Xiaoqiong Su

  5. Shanghai Medical College of Fudan University, Shanghai, China

    Geng Shen & Shengxuan Cao

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  1. Zhihong Chen
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  2. Jue Pan
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Correspondence to Lei Zhu or Xiangdong Wang.

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The authors declare that they have no conflicts of interest.

Additional information

Zhihong Chen and Jue Pan contributed equally to this work.

Electronic supplementary material

Suppl Fig. 1

No liner correlations between IL-17+CD4+Tm cell number and several clinical characteristics (Eos, IgE and FEV1) (PDF 169 kb)

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Chen, Z., Pan, J., Jia, Y. et al. Effect of memory CD4+ T cells’ signal transducer and activator of transcription (STATs) functional shift on cytokine-releasing properties in asthma. Cell Biol Toxicol 33, 27–39 (2017). https://doi.org/10.1007/s10565-016-9357-6

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  • DOI: https://doi.org/10.1007/s10565-016-9357-6

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