Regulatory T Cells Suppress Natural Killer Cell Immunity in Patients with Human Cervical Carcinoma

Wen Chun Chang, Chao Hsu Li, Ling Hui Chu, Pei Shen Huang, Bor Ching Sheu, Su Cheng Huang

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objective To determine the functional attributes of CD4+ CD25+ regulatory T (Treg) cells by suppressing natural killer (NK) cell activity in human cervical cancer (CC). Methods Triple-color flow cytometry was used to study the phenotypic expression of CD4+ CD25+ Treg cells and NK cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs). In vitro coculture assays were performed to illustrate the cytokine immunoregulations between Treg cells and NK cells. Results Significantly lower expression ratio of NK cells and higher expression ratio of Treg cells in TILs than PBLs were found. The NK cells displayed significantly higher expression ratio of inhibitory NK receptors (CD158a, CD158b, and NKG2A) and lower expression ratio of activating NK receptors (NKG2D, NKp46, and NKp30) as well as perforin in TILs than PBLs, suggesting the suppressed cytotoxicity of the NK cells in the CC tumor milieu. The expression ratio of transforming growth factor-β1 (TGF-β1) on Treg cells as well as TGF-βRII on Treg cells and NK cells was significantly higher in TILs than PBLs. Further functional in vitro assays demonstrated that NK cell function was suppressed by Treg cells, mimicking the inhibition of TGF-β on NK cells, and interleukin-2/interleukin-15 stimulation was able to restore the NK cell activity. Conclusions These findings indicate that Treg cells in TILs may abrogate NK cell cytotoxicity through TGF-β pathway, and therefore, Treg cell elimination may enhance NK cell activity and be a novel therapeutic strategy for CC.

Original languageEnglish
Pages (from-to)156-162
Number of pages7
JournalInternational Journal of Gynecological Cancer
Volume26
Issue number1
DOIs
Publication statusPublished - Jan 1 2016
Externally publishedYes

Fingerprint

Regulatory T-Lymphocytes
Natural Killer Cells
Immunity
Carcinoma
Tumor-Infiltrating Lymphocytes
Uterine Cervical Neoplasms
Lymphocytes
Natural Cytotoxicity Triggering Receptor 3
Natural Cytotoxicity Triggering Receptor 1
NK Cell Lectin-Like Receptor Subfamily K
KIR Receptors
Interleukin-15
Perforin
Transforming Growth Factors
Coculture Techniques
Human Activities
Interleukin-2
Flow Cytometry
Color
Cytokines

Keywords

  • Cervical carcinoma
  • Cytokine
  • Natural killer cells
  • Perforin
  • Regulatory T cells
  • TGF-β

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynaecology

Cite this

Regulatory T Cells Suppress Natural Killer Cell Immunity in Patients with Human Cervical Carcinoma. / Chang, Wen Chun; Li, Chao Hsu; Chu, Ling Hui; Huang, Pei Shen; Sheu, Bor Ching; Huang, Su Cheng.

In: International Journal of Gynecological Cancer, Vol. 26, No. 1, 01.01.2016, p. 156-162.

Research output: Contribution to journalArticle

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AU - Huang, Su Cheng

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N2 - Objective To determine the functional attributes of CD4+ CD25+ regulatory T (Treg) cells by suppressing natural killer (NK) cell activity in human cervical cancer (CC). Methods Triple-color flow cytometry was used to study the phenotypic expression of CD4+ CD25+ Treg cells and NK cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs). In vitro coculture assays were performed to illustrate the cytokine immunoregulations between Treg cells and NK cells. Results Significantly lower expression ratio of NK cells and higher expression ratio of Treg cells in TILs than PBLs were found. The NK cells displayed significantly higher expression ratio of inhibitory NK receptors (CD158a, CD158b, and NKG2A) and lower expression ratio of activating NK receptors (NKG2D, NKp46, and NKp30) as well as perforin in TILs than PBLs, suggesting the suppressed cytotoxicity of the NK cells in the CC tumor milieu. The expression ratio of transforming growth factor-β1 (TGF-β1) on Treg cells as well as TGF-βRII on Treg cells and NK cells was significantly higher in TILs than PBLs. Further functional in vitro assays demonstrated that NK cell function was suppressed by Treg cells, mimicking the inhibition of TGF-β on NK cells, and interleukin-2/interleukin-15 stimulation was able to restore the NK cell activity. Conclusions These findings indicate that Treg cells in TILs may abrogate NK cell cytotoxicity through TGF-β pathway, and therefore, Treg cell elimination may enhance NK cell activity and be a novel therapeutic strategy for CC.

AB - Objective To determine the functional attributes of CD4+ CD25+ regulatory T (Treg) cells by suppressing natural killer (NK) cell activity in human cervical cancer (CC). Methods Triple-color flow cytometry was used to study the phenotypic expression of CD4+ CD25+ Treg cells and NK cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs). In vitro coculture assays were performed to illustrate the cytokine immunoregulations between Treg cells and NK cells. Results Significantly lower expression ratio of NK cells and higher expression ratio of Treg cells in TILs than PBLs were found. The NK cells displayed significantly higher expression ratio of inhibitory NK receptors (CD158a, CD158b, and NKG2A) and lower expression ratio of activating NK receptors (NKG2D, NKp46, and NKp30) as well as perforin in TILs than PBLs, suggesting the suppressed cytotoxicity of the NK cells in the CC tumor milieu. The expression ratio of transforming growth factor-β1 (TGF-β1) on Treg cells as well as TGF-βRII on Treg cells and NK cells was significantly higher in TILs than PBLs. Further functional in vitro assays demonstrated that NK cell function was suppressed by Treg cells, mimicking the inhibition of TGF-β on NK cells, and interleukin-2/interleukin-15 stimulation was able to restore the NK cell activity. Conclusions These findings indicate that Treg cells in TILs may abrogate NK cell cytotoxicity through TGF-β pathway, and therefore, Treg cell elimination may enhance NK cell activity and be a novel therapeutic strategy for CC.

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