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Published in: Inflammation 3/2015

01-06-2015

Regulatory T Cells Contribute to the Recovery of Acute Lung Injury by Upregulating Tim-3

Authors: Haihan Song, Yujia Zhou, Guanggang Li, Jianwen Bai

Published in: Inflammation | Issue 3/2015

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Abstract

Acute lung injury (ALI) is characterized by alveolar injury and uncontrolled inflammation. Mechanisms underlying pathogenesis of ALI are unknown. Regulatory T cells (Tregs), either natural or induced, suppress a variety of physiological and pathological immune responses. In the current study, we investigated whether Tregs were involved in the development of ALI. Proportion of CD4 + CD25 + FoxP3+ Tregs in the peripheral blood of 66 ALI patients and 30 healthy controls were examined by flow cytometry. Data showed that the percentage of Tregs in CD4+ T cells was significantly increased in patients than that in controls (10.8 versus 7.6 %, P = 0.003). Also, compared to those who died during the study, patients who survived presented significantly higher level of Tregs at the time of recruitment (P = 0.041). Since Tim-3 is a negative regulatory molecule and can modulate the function of Tregs, we evaluated Tim-3 level on Tregs and identified upregulation of the molecule in patients than that in controls. Moreover, compared to those who died during the study, patients who survived showed 1.7-fold higher level of Tim-3 on Tregs at the time of recruitment (P < 0.001). These results suggest that Tregs could affect the prognosis of ALI probably due to the upregulation of Tim-3.
Literature
1.
go back to reference Stephens, R.S., A.S. Shah, and G.J. Whitman. 2013. Lung injury and acute respiratory distress syndrome after cardiac surgery. The Annals of Thoracic Surgery 95: 1122–1129.CrossRefPubMed Stephens, R.S., A.S. Shah, and G.J. Whitman. 2013. Lung injury and acute respiratory distress syndrome after cardiac surgery. The Annals of Thoracic Surgery 95: 1122–1129.CrossRefPubMed
3.
go back to reference Eves, N.D., N.D. Eves, Y. Song, A. Piper, and T.M. Maher. 2013. Year in review 2012: acute lung injury, interstitial lung diseases, sleep and physiology. Respirology (Carlton, Vic.) 18: 555–564.CrossRef Eves, N.D., N.D. Eves, Y. Song, A. Piper, and T.M. Maher. 2013. Year in review 2012: acute lung injury, interstitial lung diseases, sleep and physiology. Respirology (Carlton, Vic.) 18: 555–564.CrossRef
4.
go back to reference D’Alessio, F.R., K. Tsushima, N.R. Aggarwal, E.E. West, M.H. Willett, M.F. Britos, M.R. Pipeling, R.G. Brower, R.M. Tuder, J.F. McDyer, and L.S. King. 2009. CD4 + CD25 + Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. The Journal of Clinical Investigation 119: 2898–2913.CrossRefPubMedCentralPubMed D’Alessio, F.R., K. Tsushima, N.R. Aggarwal, E.E. West, M.H. Willett, M.F. Britos, M.R. Pipeling, R.G. Brower, R.M. Tuder, J.F. McDyer, and L.S. King. 2009. CD4 + CD25 + Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. The Journal of Clinical Investigation 119: 2898–2913.CrossRefPubMedCentralPubMed
5.
go back to reference Sakaguchi, S., K. Wing, and M. Miyara. 2007. Regulatory T cells - a brief history and perspective. European Journal of Immunology 37(Suppl 1): S116–123.CrossRefPubMed Sakaguchi, S., K. Wing, and M. Miyara. 2007. Regulatory T cells - a brief history and perspective. European Journal of Immunology 37(Suppl 1): S116–123.CrossRefPubMed
6.
go back to reference Ni Choileain, N., M. MacConmara, Y. Zang, T.J. Murphy, J.A. Mannick, and J.A. Lederer. 2006. Enhanced regulatory T cell activity is an element of the host response to injury. Journal of Immunology (Baltimore, Md. : 1950) 176: 225–236.CrossRef Ni Choileain, N., M. MacConmara, Y. Zang, T.J. Murphy, J.A. Mannick, and J.A. Lederer. 2006. Enhanced regulatory T cell activity is an element of the host response to injury. Journal of Immunology (Baltimore, Md. : 1950) 176: 225–236.CrossRef
7.
go back to reference D’Angelo, C., A. De Luca, T. Zelante, P. Bonifazi, S. Moretti, G. Giovannini, R.G. Iannitti, S. Zagarella, S. Bozza, S. Campo, G. Salvatori, and L. Romani. 2009. Exogenous pentraxin 3 restores antifungal resistance and restrains inflammation in murine chronic granulomatous disease. Journal of Immunology (Baltimore, Md. : 1950) 183: 4609–4618.CrossRef D’Angelo, C., A. De Luca, T. Zelante, P. Bonifazi, S. Moretti, G. Giovannini, R.G. Iannitti, S. Zagarella, S. Bozza, S. Campo, G. Salvatori, and L. Romani. 2009. Exogenous pentraxin 3 restores antifungal resistance and restrains inflammation in murine chronic granulomatous disease. Journal of Immunology (Baltimore, Md. : 1950) 183: 4609–4618.CrossRef
8.
go back to reference Monney, L., C.A. Sabatos, J.L. Gaglia, A. Ryu, H. Waldner, T. Chernova, S. Manning, E.A. Greenfield, A.J. Coyle, R.A. Sobel, G.J. Freeman, and V.K. Kuchroo. 2002. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415: 536–541.CrossRefPubMed Monney, L., C.A. Sabatos, J.L. Gaglia, A. Ryu, H. Waldner, T. Chernova, S. Manning, E.A. Greenfield, A.J. Coyle, R.A. Sobel, G.J. Freeman, and V.K. Kuchroo. 2002. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415: 536–541.CrossRefPubMed
9.
go back to reference Bai, J., X. Li, D. Tong, W. Shi, H. Song, and Q. Li. 2013. T-cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and prognosis of non-small-cell lung cancer. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine 34: 805–809.CrossRef Bai, J., X. Li, D. Tong, W. Shi, H. Song, and Q. Li. 2013. T-cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and prognosis of non-small-cell lung cancer. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine 34: 805–809.CrossRef
10.
go back to reference Song, H., S. Ma, Z. Cha, L. Chen, D. Tong, L. Ma, W. Song, and J. Bai. 2013. T-cell immunoglobulin- and mucin-domain-containing molecule 3 genetic variants and HIV+ non-Hodgkin lymphomas. Inflammation 36: 793–799.CrossRefPubMed Song, H., S. Ma, Z. Cha, L. Chen, D. Tong, L. Ma, W. Song, and J. Bai. 2013. T-cell immunoglobulin- and mucin-domain-containing molecule 3 genetic variants and HIV+ non-Hodgkin lymphomas. Inflammation 36: 793–799.CrossRefPubMed
11.
go back to reference Fernandez-Ponce, C., M. Dominguez-Villar, E. Aguado, and F. Garcia-Cozar. 2014. CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells. PLoS One 9: e85191.CrossRefPubMedCentralPubMed Fernandez-Ponce, C., M. Dominguez-Villar, E. Aguado, and F. Garcia-Cozar. 2014. CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells. PLoS One 9: e85191.CrossRefPubMedCentralPubMed
12.
go back to reference Wang, J.P., Y. Zhang, X. Wei, J. Li, X.P. Nan, H.T. Yu, Y. Li, P.Z. Wang, and X.F. Bai. 2010. Circulating Toll-like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis C. APMIS : Acta Pathologica, Microbiologica, et Immunologica Scandinavica 118: 261–270.CrossRefPubMed Wang, J.P., Y. Zhang, X. Wei, J. Li, X.P. Nan, H.T. Yu, Y. Li, P.Z. Wang, and X.F. Bai. 2010. Circulating Toll-like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis C. APMIS : Acta Pathologica, Microbiologica, et Immunologica Scandinavica 118: 261–270.CrossRefPubMed
13.
go back to reference Cai, L., Y. Fu, and Y. Zhang. 2014. APE1 Asp148Glu polymorphism and lung cancer susceptibility. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine 35: 5237–5244.CrossRef Cai, L., Y. Fu, and Y. Zhang. 2014. APE1 Asp148Glu polymorphism and lung cancer susceptibility. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine 35: 5237–5244.CrossRef
14.
go back to reference Gu, X.Y., J. Wang, Y.Z. Luo, Q. Du, R.R. Li, H. Shi, and T.P. Yu. 2014. Down-regulation of miR-150 induces cell proliferation inhibition and apoptosis in non-small-cell lung cancer by targeting BAK1 in vitro. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine 35: 5287–5293.CrossRef Gu, X.Y., J. Wang, Y.Z. Luo, Q. Du, R.R. Li, H. Shi, and T.P. Yu. 2014. Down-regulation of miR-150 induces cell proliferation inhibition and apoptosis in non-small-cell lung cancer by targeting BAK1 in vitro. Tumour Biology : The Journal of the International Society for Oncodevelopmental Biology and Medicine 35: 5287–5293.CrossRef
15.
go back to reference Han, S., S. Feng, L. Xu, W. Shi, X. Wang, H. Wang, C. Yu, T. Dong, M. Xu, and G. Liang. 2014. Tim-3 on peripheral CD4(+) and CD8(+) T cells is involved in the development of glioma. DNA and Cell Biology 33: 245–250.CrossRefPubMed Han, S., S. Feng, L. Xu, W. Shi, X. Wang, H. Wang, C. Yu, T. Dong, M. Xu, and G. Liang. 2014. Tim-3 on peripheral CD4(+) and CD8(+) T cells is involved in the development of glioma. DNA and Cell Biology 33: 245–250.CrossRefPubMed
16.
go back to reference Wu, J., C. Liu, S. Qian, and H. Hou. 2013. The expression of Tim-3 in peripheral blood of ovarian cancer. DNA and Cell Biology 32: 648–653.CrossRefPubMed Wu, J., C. Liu, S. Qian, and H. Hou. 2013. The expression of Tim-3 in peripheral blood of ovarian cancer. DNA and Cell Biology 32: 648–653.CrossRefPubMed
17.
go back to reference Lee, J., E.J. Park, J.W. Noh, J.W. Hwang, E.K. Bae, J.K. Ahn, E.M. Koh, and H.S. Cha. 2012. Underexpression of TIM-3 and blunted galectin-9-induced apoptosis of CD4+ T cells in rheumatoid arthritis. Inflammation 35: 633–637.CrossRefPubMed Lee, J., E.J. Park, J.W. Noh, J.W. Hwang, E.K. Bae, J.K. Ahn, E.M. Koh, and H.S. Cha. 2012. Underexpression of TIM-3 and blunted galectin-9-induced apoptosis of CD4+ T cells in rheumatoid arthritis. Inflammation 35: 633–637.CrossRefPubMed
18.
go back to reference Lu, X.X., K.S. McCoy, J.L. Xu, W.K. Hu, and H.B. Chen. 2013. Small interfering RNA targeting T-cell Ig mucin-3 decreases allergic airway inflammation and hyperresponsiveness. Inflammation 36: 582–591.CrossRefPubMed Lu, X.X., K.S. McCoy, J.L. Xu, W.K. Hu, and H.B. Chen. 2013. Small interfering RNA targeting T-cell Ig mucin-3 decreases allergic airway inflammation and hyperresponsiveness. Inflammation 36: 582–591.CrossRefPubMed
19.
go back to reference Bhorade, S.M., H. Chen, L. Molinero, C. Liao, E.R. Garrity, W.T. Vigneswaran, R. Shilling, A. Sperling, A. Chong, and M.L. Alegre. 2010. Decreased percentage of CD4 + FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome. Transplantation 90: 540–546.CrossRefPubMed Bhorade, S.M., H. Chen, L. Molinero, C. Liao, E.R. Garrity, W.T. Vigneswaran, R. Shilling, A. Sperling, A. Chong, and M.L. Alegre. 2010. Decreased percentage of CD4 + FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome. Transplantation 90: 540–546.CrossRefPubMed
20.
go back to reference Sun, J., Z.B. Han, W. Liao, S.G. Yang, Z. Yang, J. Yu, L. Meng, R. Wu, and Z.C. Han. 2011. Intrapulmonary delivery of human umbilical cord mesenchymal stem cells attenuates acute lung injury by expanding CD4 + CD25+ Forkhead Boxp3 (FOXP3) + regulatory T cells and balancing anti- and pro-inflammatory factors. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 27: 587–596.CrossRef Sun, J., Z.B. Han, W. Liao, S.G. Yang, Z. Yang, J. Yu, L. Meng, R. Wu, and Z.C. Han. 2011. Intrapulmonary delivery of human umbilical cord mesenchymal stem cells attenuates acute lung injury by expanding CD4 + CD25+ Forkhead Boxp3 (FOXP3) + regulatory T cells and balancing anti- and pro-inflammatory factors. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 27: 587–596.CrossRef
21.
go back to reference Holm, T.L., J. Nielsen, and M.H. Claesson. 2004. CD4 + CD25+ regulatory T cells: I. Phenotype and physiology. APMIS : Acta Pathologica, Microbiologica, et Immunologica Scandinavica 112: 629–641.CrossRefPubMed Holm, T.L., J. Nielsen, and M.H. Claesson. 2004. CD4 + CD25+ regulatory T cells: I. Phenotype and physiology. APMIS : Acta Pathologica, Microbiologica, et Immunologica Scandinavica 112: 629–641.CrossRefPubMed
22.
go back to reference Nielsen, J., T.L. Holm, and M.H. Claesson. 2004. CD4 + CD25+ regulatory T cells: II. Origin, disease models and clinical aspects. APMIS : Acta Pathologica, Microbiologica, et Immunologica Scandinavica 112: 642–650.CrossRefPubMed Nielsen, J., T.L. Holm, and M.H. Claesson. 2004. CD4 + CD25+ regulatory T cells: II. Origin, disease models and clinical aspects. APMIS : Acta Pathologica, Microbiologica, et Immunologica Scandinavica 112: 642–650.CrossRefPubMed
23.
go back to reference Tang, L., J. Bai, C.S. Chung, J. Lomas-Neira, Y. Chen, X. Huang, and A. Ayala. 2014. Active players in resolution of shock/sepsis induced indirect lung injury: immunomodulatory effects of Tregs and PD-1. Journal of Leukocyte Biology 96: 809–20.CrossRefPubMed Tang, L., J. Bai, C.S. Chung, J. Lomas-Neira, Y. Chen, X. Huang, and A. Ayala. 2014. Active players in resolution of shock/sepsis induced indirect lung injury: immunomodulatory effects of Tregs and PD-1. Journal of Leukocyte Biology 96: 809–20.CrossRefPubMed
24.
go back to reference Tang, L., L. Tang, J. Bai, C.S. Chung, J. Lomas-Neira, Y. Chen, X. Huang, and A. Ayala. 2014. PD-L1 regulates the Tregs’ capacity to repress shock/sepsis induced indirect lung injury (iALI) by recruiting phosphatase SHP-1. Shock (Augusta, Ga.). doi:10.1189/4MA1213-647RR. Tang, L., L. Tang, J. Bai, C.S. Chung, J. Lomas-Neira, Y. Chen, X. Huang, and A. Ayala. 2014. PD-L1 regulates the Tregs’ capacity to repress shock/sepsis induced indirect lung injury (iALI) by recruiting phosphatase SHP-1. Shock (Augusta, Ga.). doi:10.​1189/​4MA1213-647RR.
Metadata
Title
Regulatory T Cells Contribute to the Recovery of Acute Lung Injury by Upregulating Tim-3
Authors
Haihan Song
Yujia Zhou
Guanggang Li
Jianwen Bai
Publication date
01-06-2015
Publisher
Springer US
Published in
Inflammation / Issue 3/2015
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-014-0096-7

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