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Development of Auto Antigen-specific Regulatory T Cells for Diabetes Immunotherapy

  • Jianxun Song (Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine)
  • Received : 2016.07.26
  • Accepted : 2016.08.30
  • Published : 2016.10.31
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Abstract

CD4+ regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead to the development of autoimmune diseases, such as type-1 diabetes (T1D). T1D is a T cell-mediated autoimmune disease characterized by islet b cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. Tregs play a critical role in the development of T1D and participate in peripheral tolerance. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat T1D as they have the ability to produce almost all cell types in the body, including Tregs. However, the right conditions for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) remain undefined, especially molecular mechanisms that direct differentiation of such Tregs. Auto Ag-specific PSC-Tregs can be programmed to be tissue-associated and infiltrate to local inflamed tissue (e.g., islets) to suppress autoimmune responses after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. Developing auto Ag-specific PSC-Tregs can reduce overall immunosuppression after adoptive transfer by accumulating inflamed islets, which drives forward the use of therapeutic PSC-Tregs for cell-based therapies in T1D.

Keywords

Acknowledgement

This project is funded, in part, under grants with the National Institute of Health Grant R01AI121180, R21AI109239 and K18CA151798, American Diabetes Association 1-16-IBS-281 and the Pennsylvania Department of Health using Tobacco Settlement Funds.

References

  1. Bluestone, J. A., J. H. Buckner, M. Fitch, S. E. Gitelman, S. Gupta, M. K. Hellerstein, K. C. Herold, A. Lares, M. R. Lee, K. Li, W. Liu, S. A. Long, L. M. Masiello, V. Nguyen, A. L. Putnam, M. Rieck, P. H. Sayre, and Q. Tang. 2015. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med. 7: 315ra189. 
  2. Mahne, A. E., J. E. Klementowicz, A. Chou, V. Nguyen, and Q. Tang. 2015. Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes. J. Immunol. 194: 3147-3155.  https://doi.org/10.4049/jimmunol.1402739
  3. Hossain, D. M., A. K. Panda, A. Manna, S. Mohanty, P. Bhattacharjee, S. Bhattacharyya, T. Saha, S. Chakraborty, R. K. Kar, T. Das, S. Chatterjee, and G. Sa. 2013. FoxP3 acts as a cotranscription factor with STAT3 in tumor-induced regulatory T cells. Immunity 39: 1057-1069.  https://doi.org/10.1016/j.immuni.2013.11.005
  4. Aschenbrenner, K., L. M. D'Cruz, E. H. Vollmann, M. Hinterberger, J. Emmerich, L. K. Swee, A. Rolink, and L. Klein. 2007. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8: 351-358.  https://doi.org/10.1038/ni1444
  5. Haque, R., F. Lei, X. Xiong, Y. Wu, and J. Song. 2010. FoxP3 and Bcl-xL cooperatively promote regulatory T cell persistence and prevention of arthritis development. Arthritis Res. Ther. 12: R66. 
  6. van Herwijnen, M. J., L. Wieten, Z. R. van der, P. J. van Kooten, J. P. Wagenaar-Hilbers, A. Hoek, B. den, I, S. M. Anderton, M. Singh, H. D. Meiring, C. A. van Els, E. W. van, and F. Broere. 2012. Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis. Proc. Natl. Acad. Sci. U. S. A. 109: 14134-14139.  https://doi.org/10.1073/pnas.1206803109
  7. Wright, G. P., C. A. Notley, S. A. Xue, G. M. Bendle, A. Holler, T. N. Schumacher, M. R. Ehrenstein, and H. J. Stauss. 2009. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc. Natl. Acad. Sci. U. S. A. 106: 19078-19083.  https://doi.org/10.1073/pnas.0907396106
  8. Sela, U., P. Olds, A. Park, S. J. Schlesinger, and R. M. Steinman. 2011. Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice. J. Exp. Med. 208: 2489-2496.  https://doi.org/10.1084/jem.20110466
  9. Bacher, P., O. Kniemeyer, A. Schonbrunn, B. Sawitzki, M. Assenmacher, E. Rietschel, A. Steinbach, O. A. Cornely, A. A. Brakhage, A. Thiel, and A. Scheffold. 2014. Antigen-specific expansion of human regulatory T cells as a major tolerance mechanism against mucosal fungi. Mucosal Immunol. 7: 916-928.  https://doi.org/10.1038/mi.2013.107
  10. Nguyen, T. L., N. L. Sullivan, M. Ebel, R. M. Teague, and R. J. DiPaolo. 2011. Antigen-specific TGF-beta-induced regulatory T cells secrete chemokines, regulate T cell trafficking, and suppress ongoing autoimmunity. J. Immunol. 187: 1745-1753.  https://doi.org/10.4049/jimmunol.1004112
  11. Haque, M., J. Song, K. Fino, P. Sandhu, X. Song, F. Lei, S. Zheng, B. Ni, D. Fang, and J. Song. 2016. Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity. Sci. Rep. 6: 20588. 
  12. Van Belle, T. L., E. Ling, C. Haase, D. Bresson, B. Urso, and M. G. von Herrath. 2013. NKG2D blockade facilitates diabetes prevention by antigen-specific Tregs in a virus-induced model of diabetes. J. Autoimmun. 40: 66-73.  https://doi.org/10.1016/j.jaut.2012.08.001
  13. Takiishi, T., H. Korf, T. L. Van Belle, S. Robert, F. A. Grieco, S. Caluwaerts, L. Galleri, I. Spagnuolo, L. Steidler, H. K. Van, P. Demetter, C. Wasserfall, M. A. Atkinson, F. Dotta, P. Rottiers, C. Gysemans, and C. Mathieu. 2012. Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. J. Clin. Invest. 122: 1717-1725.  https://doi.org/10.1172/JCI60530
  14. Vogtenhuber, C., M. J. O'Shaughnessy, D. A. Vignali, and B. R. Blazar. 2008. Outgrowth of CD4low/negCD25+ T cells with suppressor function in CD4+CD25+ T cell cultures upon polyclonal stimulation ex vivo. J. Immunol. 181: 8767-8775.  https://doi.org/10.4049/jimmunol.181.12.8767
  15. Sharma, M. D., L. Huang, J. H. Choi, E. J. Lee, J. M. Wilson, H. Lemos, F. Pan, B. R. Blazar, D. M. Pardoll, A. L. Mellor, H. Shi, and D. H. Munn. 2013. An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38: 998-1012.  https://doi.org/10.1016/j.immuni.2013.01.013
  16. Perro, M., J. Tsang, S. A. Xue, D. Escors, M. Cesco-Gaspere, C. Pospori, L. Gao, D. Hart, M. Collins, H. Stauss, and E. C. Morris. 2010. Generation of multi-functional antigen-specific human T-cells by lentiviral TCR gene transfer. Gene Ther. 17: 721-732.  https://doi.org/10.1038/gt.2010.4
  17. Porter, D. L., B. L. Levine, M. Kalos, A. Bagg, and C. H. June. 2011. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365: 725-733.  https://doi.org/10.1056/NEJMoa1103849
  18. Bendle, G. M., C. Linnemann, A. I. Hooijkaas, L. Bies, M. A. de Witte, A. Jorritsma, A. D. Kaiser, N. Pouw, R. Debets, E. Kieback, W. Uckert, J. Y. Song, J. B. Haanen, and T. N. Schumacher. 2010. Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat. Med. 16: 565-70.  https://doi.org/10.1038/nm.2128
  19. Gratz, I. K., H. A. Truong, S. H. Yang, M. M. Maurano, K. Lee, A. K. Abbas, and M. D. Rosenblum. 2013. Cutting Edge: memory regulatory t cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J. Immunol. 190: 4483-4487.  https://doi.org/10.4049/jimmunol.1300212
  20. Kuball, J., M. L. Dossett, M. Wolfl, W. Y. Ho, R. H. Voss, C. Fowler, and P. D. Greenberg. 2007. Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood 109: 2331-2338.  https://doi.org/10.1182/blood-2006-05-023069
  21. van Loenen, M. M., B. R. de, A. L. Amir, R. S. Hagedoorn, G. L. Volbeda, R. Willemze, J. J. van Rood, J. H. Falkenburg, and M. H. Heemskerk. 2010. Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc. Natl. Acad. Sci. U. S. A. 107: 10972-10977.  https://doi.org/10.1073/pnas.1005802107
  22. Kim, Y. C., A. H. Zhang, Y. Su, S. A. Rieder, R. J. Rossi, R. A. Ettinger, K. P. Pratt, E. M. Shevach, and D. W. Scott. 2015. Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses. Blood 125: 1107-1115.  https://doi.org/10.1182/blood-2014-04-566786
  23. Haque, R., F. Lei, X. Xiong, Y. Bian, B. Zhao, Y. Wu, and J. Song. 2012. Programming of regulatory T cells from pluripotent stem cells and prevention of autoimmunity. J. Immunol. 189: 1228-1236.  https://doi.org/10.4049/jimmunol.1200633
  24. Kim, J. B., V. Sebastiano, G. Wu, M. J. rauzo-Bravo, P. Sasse, L. Gentile, K. Ko, D. Ruau, M. Ehrich, B. D. van den, J. Meyer, K. Hubner, C. Bernemann, C. Ortmeier, M. Zenke, B. K. Fleischmann, H. Zaehres, and H. R. Scholer. 2009. Oct4-induced pluripotency in adult neural stem cells. Cell 136: 411-419.  https://doi.org/10.1016/j.cell.2009.01.023
  25. Zhao, T., Z. N. Zhang, Z. Rong, and Y. Xu. 2011. Immunogenicity of induced pluripotent stem cells. Nature 474: 212-215.  https://doi.org/10.1038/nature10135
  26. Lei, F., B. Zhao, R. Haque, X. Xiong, L. Budgeon, N. D. Christensen, Y. Wu, and J. Song. 2011. In vivo programming of tumor antigen-specific T lymphocytes from pluripotent stem cells to promote cancer immunosurveillance. Cancer Res. 71: 4742-4747. 
  27. Haque, M., J. Song, K. Fino, P. Sandhu, Y. Wang, B. Ni, D. Fang, and J. Song. 2016. Melanoma immunotherapy in mice using genetically engineered pluripotent stem cells. Cell Transplant. 25: 811-827.  https://doi.org/10.3727/096368916X690467
  28. Themeli, M., C. C. Kloss, G. Ciriello, V. D. Fedorov, F. Perna, M. Gonen, and M. Sadelain. 2013. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31: 928-933.  https://doi.org/10.1038/nbt.2678
  29. Vizcardo, R., K. Masuda, D. Yamada, T. Ikawa, K. Shimizu, S. Fujii, H. Koseki, and H. Kawamoto. 2013. Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8(+) T cells. Cell Stem Cell 12: 31-36.  https://doi.org/10.1016/j.stem.2012.12.006
  30. Saito, H., K. Okita, A. E. Chang, and F. Ito. 2016. Adoptive transfer of CD8+ T cells generated from induced pluripotent stem cells triggers regressions of large tumors along with immunological memory. Cancer Res. 76: 3473-3483.  https://doi.org/10.1158/0008-5472.CAN-15-1742
  31. Dervovic, D. D., H. C. Liang, J. L. Cannons, A. R. Elford, M. Mohtashami, P. S. Ohashi, P. L. Schwartzberg, and J. C. Zuniga-Pflucker. 2013. Cellular and molecular requirements for the selection of in vitro-generated CD8 T cells reveal a role for Notch. J. Immunol. 191: 1704-1715.  https://doi.org/10.4049/jimmunol.1300417
  32. Wendorff, A. A., U. Koch, F. T. Wunderlich, S. Wirth, C. Dubey, J. C. Bruning, H. R. MacDonald, and F. Radtke. 2010. Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation. Immunity 33: 671-684.  https://doi.org/10.1016/j.immuni.2010.11.014
  33. Guo, Y., I. Maillard, S. Chakraborti, E. V. Rothenberg, and N. A. Speck. 2008. Core binding factors are necessary for natural killer cell development and cooperate with Notch signaling during T-cell specification. Blood 112: 480-492. 
  34. Lei, F., J. Song, R. Haque, X. Xiong, D. Fang, Y. Wu, S. M. Lens, M. Croft, and J. Song. 2013. Transgenic expression of survivin compensates for OX40-deficiency in driving Th2 development and allergic inflammation. Eur. J. Immunol. 43: 1914-1924.  https://doi.org/10.1002/eji.201243081
  35. Cheng, Y., X. Ren, Y. Yuan, Y. Shan, L. Li, X. Chen, L. Zhang, Y. Takahashi, J. W. Yang, B. Han, J. Liao, Y. Li, H. Harvey, A. Ryazanov, G. P. Robertson, G. Wan, D. Liu, A. F. Chen, Y. Tao, and J. M. Yang. 2016. eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis. Oncogene doi: 10.1038/onc.2016.166. 
  36. Di, S. A., S. K. Tey, G. Dotti, Y. Fujita, A. Kennedy-Nasser, C. Martinez, K. Straathof, E. Liu, A. G. Durett, B. Grilley, H. Liu, C. R. Cruz, B. Savoldo, A. P. Gee, J. Schindler, R. A. Krance, H. E. Heslop, D. M. Spencer, C. M. Rooney, and M. K. Brenner. 2011. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365: 1673-1683. https://doi.org/10.1056/NEJMoa1106152