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Interaction of TIM4 and TIM3 induces T helper 1 cell apoptosis

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Abstract

The T helper 1 (Th1) polarization plays a critical role in the pathogenesis of a number of inflammatory disorders in the body; the remedies in the correction of polarized Th1 cells are limited. This study aims to investigate the role of T cell immunoglobulin mucin domain molecule 4 (TIM4) in the induction of Th1 cell apoptosis. In this study, polarized Th1 cells were generated from naive Th1 cells from the mouse spleen. Recombinant TIM4 was added to the culture to stimulate the polarized Th1 cells. The apoptosis of Th1 cells was assessed by flow cytometry. The expression of FasL was analyzed by chromatin immunoprecipitation, real time RT-PCR, and Western blotting. The results showed that the polarized Th1 cells expressed high levels of TIM3. After exposure of the polarized Th1 cells to TIM4 in the culture, a complex of TIM3 and TIM4 was detected on the surface of Th1 cells, which induced the Th1 cell apoptosis. The engagement of TIM3 by TIM4 increased p300 phosphorylation in Th1 cells, which further increased the levels of Fas ligand in the cells and induced Th1 cell apoptosis. In conclusion, TIM4 binds TIM3 on the surface of polarized Th1 cells to induce Th1 cell apoptosis, which may contribute to the development of Th2-dominant immune disorders.

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References

  1. Olsen T, Rismo R, Cui G, Goll R, Christiansen I, Florholmen J. TH1 and TH17 interactions in untreated inflamed mucosa of inflammatory bowel disease, and their potential to mediate the inflammation. Cytokine. 2011;56:633.

    Article  CAS  PubMed  Google Scholar 

  2. Poole JA, Gleason AM, Bauer C, West WW, Alexis N, Reynolds SJ, Romberger DJ, Kielian T. Gamma/delta T cells and a mixed Th1/Th17 response are important in organic dust-induced airway disease. Ann Allergy Asthma Immunol. 2012;109:266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fuchs Y, Steller H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol. 2015;16:329.

    Article  CAS  PubMed  Google Scholar 

  4. Lalaoui N, Lindqvist LM, Sandow JJ, Ekert PG. The molecular relationships between apoptosis, autophagy and necroptosis. Semin Cell Dev Biol. 2015;39:63.

    Article  CAS  PubMed  Google Scholar 

  5. Arakaki R, Yamada A, Kudo Y, Hayashi Y, Ishimaru N. Mechanism of activation-induced cell death of T cells and regulation of FasL expression. Crit Rev Immunol. 2014;34:301.

    Article  CAS  PubMed  Google Scholar 

  6. Han G, Chen G, Shen B, Li Y. Tim-3: An activation marker and activation limiter of innate immune cells. Front Immunol. 2013;4:449. doi:10.3389/fimmu.2013.00449.

  7. Wu W, Shi Y, Li S, Zhang Y, Liu Y, Wu Y, Chen Z. Blockade of Tim-3 signaling restores the virus-specific CD8+ T-cell response in patients with chronic hepatitis B. Eur J Immunol. 2012;42:1180.

    Article  CAS  PubMed  Google Scholar 

  8. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536.

    Article  CAS  PubMed  Google Scholar 

  9. Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colgan JD, Hirashima M, Uede T, Takaoka A, Yagita H, Jinushi M. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol. 2012;13:832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ndhlovu LC, Lopez-Vergès L, Barbour JD, Jones RB, Jha AR, Long BR, Schoeffler EC, Fujita T, Nixon DF, Lanier LL. Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood. 2012;119:3734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tang ZH, Liang S, Potter J, Jiang X, Mao HQ, Li Z. Tim-3/galectin-9 regulate the homeostasis of hepatic NKT cells in a murine model of nonalcoholic fatty liver disease. J Immunol. 2013;190:1788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Meyers JH, Chakravarti S, Schlesinger D, Illes Z, Waldner H, Umetsu SE, Kenny J, Zheng XX, Umetsu DT, DeKruyff RH, Strom TB, Kuchroo VK. TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation. Nat Immunol. 2005;6:455.

    Article  CAS  PubMed  Google Scholar 

  13. Feng BS, Chen X, He SH, Zheng PY, Foster J, Xing Z, Bienenstock J, Yang PC. Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)1/TIM4 interaction as a therapeutic strategy in a dendritic cell-induced peanut allergy model. J Allergy Clin Immunol. 2008;122:55.

    Article  CAS  PubMed  Google Scholar 

  14. Luz-Crawford P, Kurte M, Bravo-Alegria J, Contreras R, Nova-Lamperti E, Tejedor G, Noel D, Jorgensen C, Figueroa F, Djouad F, Carrion F. Mesenchymal stem cells generate a CD4+ CD25+ Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther. 2013;4:65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245.

    Article  CAS  PubMed  Google Scholar 

  16. Dixit D, Ghildiyal R, Anto NP, Sen E. Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism. Cell Death Dis. 2014;5:e1212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang Y, Zhang Y, Gu W, He L, Sun B. Th1/Th2 cell’s function in immune system. Adv Exp Med Biol. 2014;841:45.

    Article  PubMed  Google Scholar 

  18. Lakatos L. Immunology of inflammatory bowel diseases. Acta Physiol Hung. 2000;87:355.

    CAS  PubMed  Google Scholar 

  19. Yang PC, Xing Z, Berin CM, Soderholm JD, Feng BS, Wu L, Yeh C. TIM-4 expressed by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differentiation and intestinal allergy. Gastroenterology. 2007;133:1522.

    Article  CAS  PubMed  Google Scholar 

  20. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S. Identification of Tim4 as a phosphatidylserine receptor. Nature. 2007;450:435.

    Article  CAS  PubMed  Google Scholar 

  21. Kobayashi N, Karisola P, Peña-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity. 2007;27:927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rodriguez-Manzanet R, DeKruyff R, Kuchroo VK, Umetsu DT. The costimulatory role of TIM molecules. Immunol Rev. 2009;229:259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhao G, Zhou S, Davie A, Su Q. Effects of moderate and high intensity exercise on T1/T2 balance. Exerc Immunol Rev. 2012;18:98.

    PubMed  Google Scholar 

  24. Meek DW. Regulation of the p53 response and its relationship to cancer. Biochem J. 2015;469:325.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Natural Science Foundation of SZU (No.000004), the innovation of science and Technology Commission of Shenzhen Municipality (No.JCYJ20140418095735538; JCYJ20140411150916749; JCYJ20120613173913654; JCYJ20130329110735981; JCYJ20120613173233810), International Collaboration Project (GJHZ20130408174112021), the Natural Science Foundation of China (81373176, 31400856, 31570932, 81571790 and 81501573), and Canadian Institutes of Health Research (CIHR; #191063, #220058).

Author contribution

RTG, LZ, LHM, LZX, and HPZ performed the experiments, analyzed data, and reviewed the manuscript. ZJL, ZGL, and PCY organized the study and supervised the experiments. PCY designed the project and wrote the paper.

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    Authors and Affiliations

    1. Department of Gastroenterology, The Shanghai Tenth People’s Hospital of Tongji University, Shanghai, 200072, China

      Rong-Ti Ge & Zhan-Ju Liu

    2. Shenzhen Key Laboratory of Allergy and Immunology, The Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, 518060, China

      Lu Zeng, Li-Hua Mo, Ling-Zhi Xu, Hai-Qiong Yu, Zhi-Gang Liu & Ping-Chang Yang

    3. Department of Respirology, The First Affiliated Hospital, Shenzhen University, Shenzhen, China

      Min Zhang

    4. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada

      Rong-Ti Ge, Huan-Ping Zhang & Ping-Chang Yang

    5. Shenzhen University, Room 722 of Medical School, 3688 Nanhai Blvd., Shenzhen, 518060, China

      Zhi-Gang Liu & Ping-Chang Yang

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    1. Rong-Ti Ge
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    2. Lu Zeng
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    Correspondence to Zhi-Gang Liu or Ping-Chang Yang.

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    Rong-Ti Ge and Zhi-Gang Liu have equally contributed to this work.

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    Ge, RT., Zeng, L., Mo, LH. et al. Interaction of TIM4 and TIM3 induces T helper 1 cell apoptosis. Immunol Res 64, 470–475 (2016). https://doi.org/10.1007/s12026-015-8702-9

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