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Open Access 01-12-2018 | Research article

IL-10⁺ NK and TGF-β⁺ NK cells play negative regulatory roles in HIV infection

Authors: Yongjun Jiang, Mei Yang, Xiaojuan Sun, Xi Chen, Meichen Ma, Xiaowan Yin, Shi Qian, Zining Zhang, Yajing Fu, Jing Liu, Xiaoxu Han, Junjie Xu, Hong Shang

Published in: BMC Infectious Diseases | Issue 1/2018

Abstract

Background

Natural killer (NK) cells play cytotoxic roles by targeting tumor cells or virus infected cells, they also play regulatory roles by secreting cytokines and chemokines. Transforming growth factor (TGF)-β and interleukin (IL)-10 are important immunosuppressive cytokines potentially related to the immune dysregulation that occurs in the infection of human immunodeficiency virus (HIV). NK cells are an important source of TGF-β and a main early producer of IL-10 in response to viral infection. Here, we evaluated the percentages of IL-10⁺ and TGF-β⁺ NK cells in HIV-infected patients relative to healthy controls (HCs).

Methods

Study participants (n = 63) included 31 antiretroviral treatment (ART)-naïve HIV-infected patients, 17 ART-treated HIV-infected patients, and 15 HIV-negative HCs. Expression of IL-10 or TGF-β in NK cells was examined by flow cytometry, and the influences of recombinant IL-10 (rIL-10) or recombinant TGF-β (rTGF-β) on NK cell function were investigated in vitro.

Results

Compared with HCs, ART-naïve HIV-infected patients had increased percentages of IL-10⁺ (2.0% vs. 0.4%, p = 0.015) and TGF-β⁺ (4.5% vs. 2.1%, p = 0.022) NK cells, and ART-treated patients also had a higher percentage of IL-10⁺ NK cells (2.5% vs. 0.4%, p = 0.002). The percentages of IL-10⁺ and TGF-β⁺ NK cells were positively correlated (r = 0.388; p = 0.010). The results of in vitro experiments demonstrated that rIL-10 and rTGF-β inhibited NK cell CD107a expression (p = 0.037 and p = 0.024, respectively), IFN-γ secretion (p = 0.006, p = 0.016, respectively), and granzyme B release after stimulation (p = 0.014, p = 0.040, respectively).

Conclusions

Our data suggest that the percentages of IL-10⁺ or TGF-β⁺ NK cells are increased in HIV-infected patients, and that rIL-10 and/or rTGF-β can inhibit NK cell functions in vitro, providing a potential therapeutic target for strategies aimed at combating HIV infection.

Cacalano NA. Regulation of natural killer cell function by STAT3. Front Immunol. 2016;7:128.CrossRefPubMedPubMedCentral

Littwitz-Salomon E, Dittmer U, Sutter K. Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells. Retrovirology. 2016;13(1):77.CrossRefPubMedPubMedCentral

Chester C, Fritsch K, Natural KHE. Killer cell immunomodulation: targeting activating, inhibitory, and co-stimulatory receptor signaling for cancer immunotherapy. Front Immunol. 2015;6:601.CrossRefPubMedPubMedCentral

Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461–9.CrossRefPubMedPubMedCentral

Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood. 2001;97(10):3146–51.CrossRefPubMed

Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22(11):633–40.CrossRefPubMed

Laouar Y, Sutterwala FS, Gorelik L, Transforming FRA. Growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol. 2005;6(6):600–7.CrossRefPubMed

Eriksson M, Meadows SK, Wira CR, Unique SCL. Phenotype of human uterine NK cells and their regulation by endogenous TGF-beta. J Leukoc Biol. 2004;76(3):667–75.CrossRefPubMed

Ostapchuk YO, Cetin EA, Perfilyeva YV, et al. Peripheral blood NK cells expressing HLA-G, IL-10 and TGF-beta in healthy donors and breast cancer patients. Cell Immunol. 2015;298(1–2):37–46.CrossRefPubMed

10.

Elrefaei M, Burke CM, Baker CA, et al. TGF-beta and IL-10 production by HIV-specific CD8+ T cells is regulated by CTLA-4 signaling on CD4+ T cells. PLoS One. 2009;4(12):e8194.CrossRefPubMedPubMedCentral

11.

Shete A, Suryawanshi P, Godbole S, Pawar J, Paranjape R, Thakar M. HIV-infected CD4+ T cells use T-bet-dependent pathway for production of IL-10 upon antigen recognition. Scand J Immunol. 2016;83(4):288–96.CrossRefPubMed

12.

Wagage S, John B, Krock BL, et al. The aryl hydrocarbon receptor promotes IL-10 production by NK cells. J Immunol. 2014;192(4):1661–70.CrossRefPubMedPubMedCentral

13.

Perona-Wright G, Mohrs K, Szaba FM, et al. Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe. 2009;6(6):503–12.CrossRefPubMedPubMedCentral

14.

Ng CT, Oldstone MB. Infected CD8alpha- dendritic cells are the predominant source of IL-10 during establishment of persistent viral infection. Proc Natl Acad Sci U S A. 2012;109(35):14116–21.CrossRefPubMedPubMedCentral

15.

Gray JD, Hirokawa M, Ohtsuka K, Horwitz DA. Generation of an inhibitory circuit involving CD8+ T cells, IL-2, and NK cell-derived TGF-beta: contrasting effects of anti-CD2 and anti-CD3. J Immunol. 1998;160(5):2248–54.PubMed

16.

Sporn MB, Roberts AB, Wakefield LM, de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987;105(3):1039–45.CrossRefPubMed

17.

Wahl SM. Transforming growth factor beta: the good, the bad, and the ugly. J Exp Med. 1994;180(5):1587–90.CrossRefPubMed

18.

Clerici M, Wynn TA, Berzofsky JA, et al. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest. 1994;93(2):768–75.CrossRefPubMedPubMedCentral

19.

Fidler SJ, Antigen RAD. Presenting cell function in HIV-1 infected patients. Immunol Lett. 1999;66(1–3):129–34.CrossRefPubMed

20.

Schols D, De Clercq E. Human immunodeficiency virus type 1 gp120 induces anergy in human peripheral blood lymphocytes by inducing interleukin-10 production. J Virol. 1996;70(8):4953–60.PubMedPubMedCentral

21.

Poggi A, Zocchi MR. HIV-1 tat triggers TGF-beta production and NK cell apoptosis that is prevented by pertussis toxin B. Clin dev immunol. 2006;13(2–4):369–72.CrossRefPubMedPubMedCentral

22.

Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med. 2006;12(11):1301–9.CrossRefPubMedPubMedCentral

23.

Park JY, Lee SH, Yoon SR, et al. IL-15-induced IL-10 increases the cytolytic activity of human natural killer cells. Molec cells. 2011;32(3):265–72.CrossRefPubMedPubMedCentral

24.

Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.CrossRefPubMed

25.

Hamidullah, Changkija B, Konwar R. Role of interleukin-10 in breast cancer. Breast Cancer Res Treat. 2012;133(1):11–21.CrossRefPubMed

26.

Crane CA, Han SJ, Barry JJ, Ahn BJ, Lanier LL, TGF-beta PAT. Downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Neuro-Oncology. 2010;12(1):7–13.CrossRefPubMed

27.

Wilson EB, El-Jawhari JJ, Neilson AL, et al. Human tumour immune evasion via TGF-beta blocks NK cell activation but not survival allowing therapeutic restoration of anti-tumour activity. PLoS One. 2011;6(9):e22842.CrossRefPubMedPubMedCentral

28.

Taylor A, Verhagen J, Blaser K, Akdis M, Mechanisms ACA. Of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology. 2006;117(4):433–42.CrossRefPubMedPubMedCentral

29.

Brockman MA, Kwon DS, Tighe DP, et al. IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood. 2009;114(2):346–56.CrossRefPubMedPubMedCentral

30.

Jiang Y, Zhou F, Tian Y, et al. Higher NK cell IFN-gamma production is associated with delayed HIV disease progression in LTNPs. J Clin Immunol. 2013;33(8):1376–85.CrossRefPubMed

31.

Qi W, Yongjun J, Yanan W, et al. Differential expression of perforin in cytotoxic lymphocyte in HIV/AIDS patients of China. J Clin Immunol. 2006;26(4):339–46.CrossRefPubMed

32.

Shete A, Thakar M, Singh DP, et al. Short communication: HIV antigen-specific reactivation of HIV infection from cellular reservoirs: implications in the settings of therapeutic vaccinations. AIDS Res Hum Retrovir. 2012;28(8):835–43.CrossRefPubMed

33.

Badou A, Bennasser Y, Moreau M, Leclerc C, Benkirane M, Tat BE. Protein of human immunodeficiency virus type 1 induces interleukin-10 in human peripheral blood monocytes: implication of protein kinase C-dependent pathway. J Virol. 2000;74(22):10551–62.CrossRefPubMedPubMedCentral

34.

Bennasser Y, Bahraoui E. HIV-1 tat protein induces interleukin-10 in human peripheral blood monocytes: involvement of protein kinase C-betaII and -delta. FASEB j : offi pub Feder Am Soc Exper Biol. 2002;16(6):546–54.CrossRef

35.

Gee K, Angel JB, Ma W, et al. Intracellular HIV-tat expression induces IL-10 synthesis by the CREB-1 transcription factor through Ser133 phosphorylation and its regulation by the ERK1/2 MAPK in human monocytic cells. J Biol Chem. 2006;281(42):31647–58.CrossRefPubMed

36.

Saraiva M, Christensen JR, Veldhoen M, Murphy TL, Murphy KM, O'Garra A. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity. 2009;31(2):209–19.CrossRefPubMedPubMedCentral

37.

Viel S, Marcais A, Guimaraes FS, et al. TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal. 2016;9(415):ra19.CrossRefPubMed

38.

Trotta R, Dal Col J, Yu J, et al. TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. J Immunol. 2008;181(6):3784–92.CrossRefPubMedPubMedCentral

Title: IL-10+ NK and TGF-β+ NK cells play negative regulatory roles in HIV infection
Authors: Yongjun Jiang
Mei Yang
Xiaojuan Sun
Xi Chen
Meichen Ma
Xiaowan Yin
Shi Qian
Zining Zhang
Yajing Fu
Jing Liu
Xiaoxu Han
Junjie Xu
Hong Shang
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Infectious Diseases / Issue 1/2018
Electronic ISSN: 1471-2334
DOI: https://doi.org/10.1186/s12879-018-2991-2

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IL-10⁺ NK and TGF-β⁺ NK cells play negative regulatory roles in HIV infection

Abstract

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Methods

Results

Conclusions

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