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Published in: BMC Immunology 1/2019

Open Access 01-12-2019 | Human Immunodeficiency Virus | Research article

Foxp3+Helios+ regulatory T cells are associated with monocyte subsets and their PD-1 expression during acute HIV-1 infection

Authors: Lifeng Liu, Qiuyue Zhang, Peng Chen, Na Guo, Aixin Song, Xiaojie Huang, Wei Xia, Li Li, Christiane Moog, Hao Wu, Bin Su, Tong Zhang

Published in: BMC Immunology | Issue 1/2019

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Abstract

Background

Helios has been reported to stabilize regulatory T (Treg) suppressive function. Programmed cell death protein 1 (PD-1) expression in three human monocyte subsets modulates immune responses. Recently, our team reported that three monocyte subsets are associated with T helper cell differentiation in HIV-1-infected patients. Until now, the effects of monocyte subsets and their PD-1 expression on Foxp3+Helios+ Treg cells have not been fully characterized, especially during acute HIV-1 infection.

Results

The frequency of Foxp3+Helios+CD45RA+ Treg cells is significantly higher in patients with acute HIV-1 infection than those of healthy controls and chronic HIV-1-infected patients undergoing combined antiretroviral therapy. The frequency of Foxp3+Helios+CD45RA+ Treg cells is inversely correlated with CD4 T-cell counts and the CD4/CD8 ratio in chronic HIV-1-infected patients. During acute HIV-1 infection, the frequency of Foxp3+Helios+CD45RA+ Treg cells is inversely correlated with the frequency of the intermediate CD14++CD16+ monocyte subset, but positively correlated with PD-1 expression in both intermediate CD14++CD16+ and non-classical CD14+CD16++ monocyte subsets.

Conclusions

In this study, the perturbations of Foxp3+Helios+ Treg cells were characterized, and the association between monocyte subsets and their PD-1 expression and Foxp3+Helios+ Treg cells was evaluated during HIV-1 infection. Our observations provide new evidence of the roles for Foxp3+Helios+ Treg cells and PD-1 expression on monocyte subsets in HIV pathogenesis.
Literature
1.
go back to reference Saison J, Ferry T, Demaret J, Maucort BD, Venet F, Perpoint T, Ader F, Icard V, Chidiac C, Monneret G. Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients. Clin Exp Immunol. 2014;176:401–9.CrossRef Saison J, Ferry T, Demaret J, Maucort BD, Venet F, Perpoint T, Ader F, Icard V, Chidiac C, Monneret G. Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients. Clin Exp Immunol. 2014;176:401–9.CrossRef
2.
go back to reference Curotto DLM, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity. 2009;30:626–35.CrossRef Curotto DLM, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity. 2009;30:626–35.CrossRef
3.
go back to reference Khaitan A, Kravietz A, Mwamzuka M, Marshed F, Ilmet T, Said S, Ahmed A, Borkowsky W, Unutmaz D. FOXP3+Helios+ regulatory T cells, immune activation, and advancing disease in HIV-infected children. J Acquir Immune Defic Syndr. 2016;72:474–84.CrossRef Khaitan A, Kravietz A, Mwamzuka M, Marshed F, Ilmet T, Said S, Ahmed A, Borkowsky W, Unutmaz D. FOXP3+Helios+ regulatory T cells, immune activation, and advancing disease in HIV-infected children. J Acquir Immune Defic Syndr. 2016;72:474–84.CrossRef
4.
go back to reference Kim HJ, Barnitz RA, Kreslavsky T, Brown FD, Moffett H, Lemieux ME, Kaygusuz Y, Meissner T, Holderried TA, Chan S, et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science. 2015;350:334–9.CrossRef Kim HJ, Barnitz RA, Kreslavsky T, Brown FD, Moffett H, Lemieux ME, Kaygusuz Y, Meissner T, Holderried TA, Chan S, et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science. 2015;350:334–9.CrossRef
5.
go back to reference Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and differences. Immunol Rev. 2014;259:88–102.CrossRef Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and differences. Immunol Rev. 2014;259:88–102.CrossRef
6.
go back to reference Mercer F, Khaitan A, Kozhaya L, Aberg JA, Unutmaz D. Differentiation of IL-17-producing effector and regulatory human T cells from lineage-committed naive precursors. J Immunol. 2014;193:1047–54.CrossRef Mercer F, Khaitan A, Kozhaya L, Aberg JA, Unutmaz D. Differentiation of IL-17-producing effector and regulatory human T cells from lineage-committed naive precursors. J Immunol. 2014;193:1047–54.CrossRef
7.
go back to reference Anzinger JJ, Butterfield TR, Angelovich TA, Crowe SM, Palmer CS. Monocytes as regulators of inflammation and HIV-related comorbidities during cART. J Immunol Res. 2014;2014:569819.CrossRef Anzinger JJ, Butterfield TR, Angelovich TA, Crowe SM, Palmer CS. Monocytes as regulators of inflammation and HIV-related comorbidities during cART. J Immunol Res. 2014;2014:569819.CrossRef
8.
go back to reference Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, Leenen PJ, Liu YJ, MacPherson G, Randolph GJ, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116:e74–80.CrossRef Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, Leenen PJ, Liu YJ, MacPherson G, Randolph GJ, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116:e74–80.CrossRef
9.
go back to reference Jakubzick CV, Randolph GJ, Henson PM. Monocyte differentiation and antigen-presenting functions. Nat Rev Immunol. 2017;17:349–62.CrossRef Jakubzick CV, Randolph GJ, Henson PM. Monocyte differentiation and antigen-presenting functions. Nat Rev Immunol. 2017;17:349–62.CrossRef
10.
go back to reference Zhong H, Yazdanbakhsh K. Differential control of Helios(+/−) Treg development by monocyte subsets through disparate inflammatory cytokines. Blood. 2013;121:2494–502.CrossRef Zhong H, Yazdanbakhsh K. Differential control of Helios(+/−) Treg development by monocyte subsets through disparate inflammatory cytokines. Blood. 2013;121:2494–502.CrossRef
11.
go back to reference Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443:350–4.CrossRef Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443:350–4.CrossRef
12.
go back to reference Saeidi A, Zandi K, Cheok YY, Saeidi H, Wong WF, Lee C, Cheong HC, Yong YK, Larsson M, Shankar EM. T-cell exhaustion in chronic infections: reversing the state of exhaustion and reinvigorating optimal protective immune responses. Front Immunol. 2018;9:2569.CrossRef Saeidi A, Zandi K, Cheok YY, Saeidi H, Wong WF, Lee C, Cheong HC, Yong YK, Larsson M, Shankar EM. T-cell exhaustion in chronic infections: reversing the state of exhaustion and reinvigorating optimal protective immune responses. Front Immunol. 2018;9:2569.CrossRef
13.
go back to reference Larsson M, Shankar EM, Che KF, Saeidi A, Ellegard R, Barathan M, Velu V, Kamarulzaman A. Molecular signatures of T-cell inhibition in HIV-1 infection. Retrovirology. 2013;10:31.CrossRef Larsson M, Shankar EM, Che KF, Saeidi A, Ellegard R, Barathan M, Velu V, Kamarulzaman A. Molecular signatures of T-cell inhibition in HIV-1 infection. Retrovirology. 2013;10:31.CrossRef
14.
go back to reference Riella LV, Paterson AM, Sharpe AH, Chandraker A. Role of the PD-1 pathway in the immune response. Am J Transplant. 2012;12:2575–87.CrossRef Riella LV, Paterson AM, Sharpe AH, Chandraker A. Role of the PD-1 pathway in the immune response. Am J Transplant. 2012;12:2575–87.CrossRef
15.
go back to reference Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC, et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med. 2006;203:2281–92.CrossRef Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC, et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med. 2006;203:2281–92.CrossRef
16.
go back to reference Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010;16:452–9.CrossRef Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010;16:452–9.CrossRef
17.
go back to reference Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1/2 pathway from discovery to clinical implementation. Front Immunol. 2016;7:550.CrossRef Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1/2 pathway from discovery to clinical implementation. Front Immunol. 2016;7:550.CrossRef
18.
go back to reference McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF. The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol. 2010;10:11–23.CrossRef McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF. The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol. 2010;10:11–23.CrossRef
19.
go back to reference Chen P, Su B, Zhang T, Zhu X, Xia W, Fu Y, Zhao G, Xia H, Dai L, Sun L, et al. Perturbations of monocyte subsets and their association with T helper cell differentiation in acute and chronic HIV-1-infected patients. Front Immunol. 2017;8:272.PubMedPubMedCentral Chen P, Su B, Zhang T, Zhu X, Xia W, Fu Y, Zhao G, Xia H, Dai L, Sun L, et al. Perturbations of monocyte subsets and their association with T helper cell differentiation in acute and chronic HIV-1-infected patients. Front Immunol. 2017;8:272.PubMedPubMedCentral
20.
go back to reference Guo N, Liu L, Yang X, Song T, Li G, Li L, Jiang T, Gao Y, Zhang T, Su B, et al. Immunological changes in monocyte subsets and their association with Foxp3(+) regulatory T cells in HIV-1-infected individuals with syphilis: a brief research report. Front Immunol. 2019;10:714.CrossRef Guo N, Liu L, Yang X, Song T, Li G, Li L, Jiang T, Gao Y, Zhang T, Su B, et al. Immunological changes in monocyte subsets and their association with Foxp3(+) regulatory T cells in HIV-1-infected individuals with syphilis: a brief research report. Front Immunol. 2019;10:714.CrossRef
21.
go back to reference Simonetta F, Lecuroux C, Girault I, Goujard C, Sinet M, Lambotte O, Venet A, Bourgeois C. Early and long-lasting alteration of effector CD45RA(−)Foxp3(high) regulatory T-cell homeostasis during HIV infection. J Infect Dis. 2012;205:1510–9.CrossRef Simonetta F, Lecuroux C, Girault I, Goujard C, Sinet M, Lambotte O, Venet A, Bourgeois C. Early and long-lasting alteration of effector CD45RA(−)Foxp3(high) regulatory T-cell homeostasis during HIV infection. J Infect Dis. 2012;205:1510–9.CrossRef
22.
go back to reference Matavele CR, Namalango E, Maphossa V, Macicame I, Bhatt N, Polyak C, Robb M, Michael N, Jani I, Kestens L. Helios + regulatory T cell frequencies are correlated with control of viral replication and recovery of absolute CD4 T cells counts in early HIV-1 infection. BMC Immunol. 2017;18:50.CrossRef Matavele CR, Namalango E, Maphossa V, Macicame I, Bhatt N, Polyak C, Robb M, Michael N, Jani I, Kestens L. Helios + regulatory T cell frequencies are correlated with control of viral replication and recovery of absolute CD4 T cells counts in early HIV-1 infection. BMC Immunol. 2017;18:50.CrossRef
23.
go back to reference Bandera A, Ferrario G, Saresella M, Marventano I, Soria A, Zanini F, Sabbatini F, Airoldi M, Marchetti G, Franzetti F, et al. CD4+ T cell depletion, immune activation and increased production of regulatory T cells in the thymus of HIV-infected individuals. PLoS One. 2010;5:e10788.CrossRef Bandera A, Ferrario G, Saresella M, Marventano I, Soria A, Zanini F, Sabbatini F, Airoldi M, Marchetti G, Franzetti F, et al. CD4+ T cell depletion, immune activation and increased production of regulatory T cells in the thymus of HIV-infected individuals. PLoS One. 2010;5:e10788.CrossRef
24.
go back to reference Fritzsching B, Oberle N, Eberhardt N, Quick S, Haas J, Wildemann B, Krammer PH, Suri-Payer E. In contrast to effector T cells, CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death. J Immunol. 2005;175:32–6.CrossRef Fritzsching B, Oberle N, Eberhardt N, Quick S, Haas J, Wildemann B, Krammer PH, Suri-Payer E. In contrast to effector T cells, CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death. J Immunol. 2005;175:32–6.CrossRef
25.
go back to reference Lim A, Tan D, Price P, Kamarulzaman A, Tan HY, James I, French MA. Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high on antiretroviral therapy. Aids. 2007;21:1525–34.CrossRef Lim A, Tan D, Price P, Kamarulzaman A, Tan HY, James I, French MA. Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high on antiretroviral therapy. Aids. 2007;21:1525–34.CrossRef
26.
go back to reference Piconi S, Trabattoni D, Gori A, Parisotto S, Magni C, Meraviglia P, Bandera A, Capetti A, Rizzardini G, Clerici M. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. Aids. 2010;24:1991–2000.CrossRef Piconi S, Trabattoni D, Gori A, Parisotto S, Magni C, Meraviglia P, Bandera A, Capetti A, Rizzardini G, Clerici M. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. Aids. 2010;24:1991–2000.CrossRef
27.
go back to reference Weiss L, Piketty C, Assoumou L, Didier C, Caccavelli L, Donkova-Petrini V, Levy Y, Girard PM, Burgard M, Viard JP, et al. Relationship between regulatory T cells and immune activation in human immunodeficiency virus-infected patients interrupting antiretroviral therapy. PLoS One. 2010;5:e11659.CrossRef Weiss L, Piketty C, Assoumou L, Didier C, Caccavelli L, Donkova-Petrini V, Levy Y, Girard PM, Burgard M, Viard JP, et al. Relationship between regulatory T cells and immune activation in human immunodeficiency virus-infected patients interrupting antiretroviral therapy. PLoS One. 2010;5:e11659.CrossRef
28.
go back to reference Yamazaki S, Inaba K, Tarbell KV, Steinman RM. Dendritic cells expand antigen-specific Foxp3+ CD25+ CD4+ regulatory T cells including suppressors of alloreactivity. Immunol Rev. 2006;212:314–29.CrossRef Yamazaki S, Inaba K, Tarbell KV, Steinman RM. Dendritic cells expand antigen-specific Foxp3+ CD25+ CD4+ regulatory T cells including suppressors of alloreactivity. Immunol Rev. 2006;212:314–29.CrossRef
29.
go back to reference Zhong H, Bao W, Li X, Miller A, Seery C, Haq N, Bussel J, Yazdanbakhsh K. CD16+ monocytes control T-cell subset development in immune thrombocytopenia. Blood. 2012;120:3326–35.CrossRef Zhong H, Bao W, Li X, Miller A, Seery C, Haq N, Bussel J, Yazdanbakhsh K. CD16+ monocytes control T-cell subset development in immune thrombocytopenia. Blood. 2012;120:3326–35.CrossRef
30.
go back to reference Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36:265–76.CrossRef Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36:265–76.CrossRef
31.
go back to reference Yao S, Wang S, Zhu Y, Luo L, Zhu G, Flies S, Xu H, Ruff W, Broadwater M, Choi IH, et al. PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood. 2009;113:5811–8.CrossRef Yao S, Wang S, Zhu Y, Luo L, Zhu G, Flies S, Xu H, Ruff W, Broadwater M, Choi IH, et al. PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood. 2009;113:5811–8.CrossRef
32.
go back to reference Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, Swan R, Kherouf H, Monneret G, Chung CS, et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A. 2009;106:6303–8.CrossRef Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, Swan R, Kherouf H, Monneret G, Chung CS, et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A. 2009;106:6303–8.CrossRef
33.
go back to reference Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJ. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A. 2008;105:9331–6.CrossRef Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJ. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A. 2008;105:9331–6.CrossRef
34.
go back to reference Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.CrossRef Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.CrossRef
35.
go back to reference Poltorak MP, Schraml BU. Fate mapping of dendritic cells. Front Immunol. 2015;6:199.CrossRef Poltorak MP, Schraml BU. Fate mapping of dendritic cells. Front Immunol. 2015;6:199.CrossRef
36.
go back to reference Tippayawat P, Pinsiri M, Rinchai D, Riyapa D, Romphruk A, Gan YH, Houghton RL, Felgner PL, Titball RW, Stevens MP, et al. Burkholderia pseudomallei proteins presented by monocyte-derived dendritic cells stimulate human memory T cells in vitro. Infect Immun. 2011;79:305–13.CrossRef Tippayawat P, Pinsiri M, Rinchai D, Riyapa D, Romphruk A, Gan YH, Houghton RL, Felgner PL, Titball RW, Stevens MP, et al. Burkholderia pseudomallei proteins presented by monocyte-derived dendritic cells stimulate human memory T cells in vitro. Infect Immun. 2011;79:305–13.CrossRef
Metadata
Title
Foxp3+Helios+ regulatory T cells are associated with monocyte subsets and their PD-1 expression during acute HIV-1 infection
Authors
Lifeng Liu
Qiuyue Zhang
Peng Chen
Na Guo
Aixin Song
Xiaojie Huang
Wei Xia
Li Li
Christiane Moog
Hao Wu
Bin Su
Tong Zhang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2019
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/s12865-019-0319-7

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