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Immunologic Research
Published in: Immunologic Research 3/2015

01-03-2015

Insufficient secretion of IL-10 by Tregs compromised its control on over-activated CD4+ T effector cells in newly diagnosed adult immune thrombocytopenia patients

Authors: Feng Li, Lili Ji, Weiguang Wang, Fanli Hua, Yanxia Zhan, Shanhua Zou, Ling Yuan, Yang Ke, Zhihui Min, Dongli Song, Lihua Sun, Hao Chen, Yunfeng Cheng

Published in: Immunologic Research | Issue 3/2015

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Abstract

Primary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder. Excessive activated CD4+ T effector cells (Teffs) and compromised regulatory T cells (Tregs) were reported in ITP patients, yet little is known about the mechanisms. Interleukin-10 (IL-10) is an important regulatory cytokine of Tregs in inflammatory condition. It has been recently highlighted that IL-10-producing Tregs contribute to the effective controls of several autoimmune diseases. Hence this study was aimed to examine the role of IL-10 produced by Tregs in newly diagnosed ITP patients. Newly diagnosed ITP patients and healthy volunteers were enrolled to assess the numbers of peripheral Th1, Th17 cells and Tregs. CD4+CD25−Teffs and CD4+CD25+Tregs were purified. CD4+CD25−Teffs, labeled with CFSE, were cultured alone or with Tregs for 5 days, and the supernatants were then collected for IL-10 concentration test. The role of IL-10 in Tregs’ inhibitory function was also determined. In ITP patients, Teffs were excessively activated, while the Tregs were numerically and functionally impaired. The percentages of IL-10+ Tregs in Tregs’ population were found elevated dramatically in ITP patients but decreased in the remitted patients. The IL-10 concentrations in the cultured supernatant were decreased in ITP patients but elevated in the remitted patients. Furthermore, the IL-10 secretion by Tregs was dramatically decreased in ITP patients. IL-10 treatment enhanced the suppression effect of Tregs toward Teffs, whereas anti-IL-10 treatment boosted the proliferation of Teffs and Th17 cells. Excessive activated Teffs and impaired Tregs play major roles in the exuberant CD4+ T cells immune responses of ITP. The inhibitory effect of Tregs toward Teffs is largely exerted by IL-10. Insufficient secretion of IL-10 compromises the inhibitory capability of Tregs against Teffs in newly diagnosed ITP patients.
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Literature
1.
Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386–93. doi:10.​1182/​blood-2008-07-162503.CrossRefPubMed
2.
Panitsas FP, Theodoropoulou M, Kouraklis A, Karakantza M, Theodorou GL, Zoumbos NC, et al. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response. Blood. 2004;103(7):2645–7. doi:10.​1182/​blood-2003-07-2268.CrossRefPubMed
3.
Pene J, Chevalier S, Preisser L, Venereau E, Guilleux MH, Ghannam S, et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol. 2008;180(11):7423–30.CrossRefPubMed
4.
Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123–32.CrossRefPubMed
5.
Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133–41.CrossRefPubMedCentralPubMed
6.
Guo ZX, Chen ZP, Zheng CL, Jia HR, Ge J, Gu DS, et al. The role of Th17 cells in adult patients with chronic idiopathic thrombocytopenic purpura. Eur J Haematol. 2009;82(6):488–9.CrossRefPubMed
7.
Sollazzo D, Trabanelli S, Curti A, Vianelli N, Lemoli RM, Catani L. Circulating CD4+ CD161+ CD196+ Th17 cells are not increased in immune thrombocytopenia. Haematologica. 2011;96(4):632–4.CrossRefPubMedCentralPubMed
8.
9.
Zhu X, Ma D, Zhang J, Peng J, Qu X, Ji C, et al. Elevated interleukin-21 correlated to Th17 and Th1 cells in patients with immune thrombocytopenia. J Clin Immunol. 2010;30(2):253–9.CrossRefPubMed
10.
Zhang J, Ma D, Zhu X, Qu X, Ji C, Hou M. Elevated profile of Th17, Th1 and Tc1 cells in patients with immune thrombocytopenic purpura. Haematologica. 2009;94(9):1326–9.CrossRefPubMedCentralPubMed
11.
12.
13.
Liu B, Zhao H, Poon MC, Han Z, Gu D, Xu M, et al. Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura. Eur J Haematol. 2007;78(2):139–43.PubMed
14.
Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636–45.CrossRefPubMed
15.
Miyara M, Gorochov G, Ehrenstein M, Musset L, Sakaguchi S, Amoura Z. Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun Rev. 2011;10(12):744–55.CrossRefPubMed
16.
Li MO, Flavell RA. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity. 2008;28(4):468–76.CrossRefPubMed
17.
18.
Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity. 2011;34(4):566–78.CrossRefPubMedCentralPubMed
19.
Huber S, Gagliani N, Esplugues E, O’Connor W Jr, Huber FJ, Chaudhry A, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3(−) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity. 2011;34(4):554–65.CrossRefPubMedCentralPubMed
20.
de Kouchkovsky D, Esensten JH, Rosenthal WL, Morar MM, Bluestone JA, Jeker LT. MicroRNA-17-92 regulates IL-10 production by regulatory T cells and control of experimental autoimmune encephalomyelitis. J Immunol. 2013;191(4):1594–605.CrossRefPubMedCentralPubMed
21.
Kornete M, Sgouroudis E, Piccirillo CA. ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice. J Immunol. 2012;188(3):1064–74.CrossRefPubMed
22.
Moon SJ, Park JS, Heo YJ, Kang CM, Kim EK, Lim MA, et al. In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis. Exp Mol Med. 2013;45:e46.CrossRefPubMedCentralPubMed
23.
Bao W, Bussel JB, Heck S, He W, Karpoff M, Boulad N, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116(22):4639–45.CrossRefPubMedCentralPubMed
24.
Stasi R, Cooper N, Del Poeta G, Stipa E, Laura Evangelista M, Abruzzese E, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood. 2008;112(4):1147–50. doi:10.​1182/​blood-2007-12-129262.CrossRefPubMed
25.
Fiorentino DF, Zlotnik A, Vieira P, Mosmann TR, Howard M, Moore KW, et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991;146(10):3444–51.PubMed
26.
Ding L, Shevach EM. IL-10 inhibits mitogen-induced T cell proliferation by selectively inhibiting macrophage costimulatory function. J Immunol. 1992;148(10):3133–9.PubMed
27.
Fitzgerald DC, Zhang GX, El-Behi M, Fonseca-Kelly Z, Li H, Yu S, et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol. 2007;8(12):1372–9.CrossRefPubMed
28.
McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007;8(12):1390–7.CrossRefPubMed
29.
Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168–86.CrossRefPubMed
30.
Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA. The american society of hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190–207.CrossRefPubMed
31.
Semple JW, Freedman J. Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood. 1991;78(10):2619–25.PubMed
32.
Ogawara H, Handa H, Morita K, Hayakawa M, Kojima J, Amagai H, et al. High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura. Eur J Haematol. 2003;71(4):283–8.CrossRefPubMed
33.
Kuwana M, Ikeda Y. The role of autoreactive T-cells in the pathogenesis of idiopathic thrombocytopenic purpura. Int J Hematol. 2005;81(2):106–12.CrossRefPubMed
34.
Saraiva M, O’Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol. 2010;10(3):170–81.CrossRefPubMed
35.
Kole A, He J, Rivollier A, Silveira DD, Kitamura K, Maloy KJ, et al. Type I IFNs regulate effector and regulatory T cell accumulation and anti-inflammatory cytokine production during T cell-mediated colitis. J Immunol. 2013;191(5):2771–9.CrossRefPubMedCentralPubMed
36.
Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol. 2007;8(12):1363–71.CrossRefPubMed
37.
Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, et al. The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity. 2012;37(3):511–23.CrossRefPubMedCentralPubMed
38.
Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol. 2009;10(11):1178–84. doi:10.​1038/​ni.​1791.CrossRefPubMedCentralPubMed
39.
40.
Naundorf S, Schroder M, Hoflich C, Suman N, Volk HD, Grutz G. IL-10 interferes directly with TCR-induced IFN-gamma but not IL-17 production in memory T cells. Eur J Immunol. 2009;39(4):1066–77.CrossRefPubMed
41.
Gu Y, Yang J, Ouyang X, Liu W, Li H, Yang J, et al. Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells. Eur J Immunol. 2008;38(7):1807–13.CrossRefPubMedCentralPubMed
42.
Huse M, Lillemeier BF, Kuhns MS, Chen DS, Davis MM. T cells use two directionally distinct pathways for cytokine secretion. Nat Immunol. 2006;7(3):247–55.CrossRefPubMed
43.
Hua F, Ji L, Zhan Y, Li F, Zou S, Wang X, et al. Pulsed high-dose dexamethasone improves interleukin 10 secretion by CD5+ B cells in patients with primary immune thrombocytopenia. J Clin Immunol. 2012;32(6):1233–42. doi:10.​1007/​s10875-012-9714-z.CrossRefPubMed
44.
Kamanaka M, Huber S, Zenewicz LA, Gagliani N, Rathinam C, O’Connor W Jr, et al. Memory/effector (CD45RB(lo)) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology. J Exp Med. 2011;208(5):1027–40.CrossRefPubMedCentralPubMed
Metadata
Title
Insufficient secretion of IL-10 by Tregs compromised its control on over-activated CD4+ T effector cells in newly diagnosed adult immune thrombocytopenia patients
Authors
Feng Li
Lili Ji
Weiguang Wang
Fanli Hua
Yanxia Zhan
Shanhua Zou
Ling Yuan
Yang Ke
Zhihui Min
Dongli Song
Lihua Sun
Hao Chen
Yunfeng Cheng
Publication date
01-03-2015
Publisher
Springer US
Published in
Immunologic Research / Issue 3/2015
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-014-8620-2

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