Abstract
The thymic microenvironment provides essential support for the generation of a functional and diverse population of human T cells. In particular, the three-dimensional (3D) thymic architecture contributes to critical cell-cell interactions. We report that thymic stroma, arrayed on a synthetic 3D matrix, supports the development of functional human T cells from hematopoietic precursor cells. Newly generated T cells contain T-cell receptor excision circles and are both fully mature and functional. The coculture of T-cell progenitors with thymic stroma can thus be used to generate de novo functional and diverse T-cell populations. This novel tissue engineered thymic system has biological applications for the study of T-lymphopoiesis and self-tolerance as well as potential therapeutic applications including the immune reconstitution of immunocompromised patients and the induction of tolerance in individuals receiving tissue or organ transplants.
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References
Platt, J. L. and Lakkis, F. G. (2001) A scenic overlook on the road to clinical tolerance. Trends Immunol. 22, 289–291.
Hogquist, K. A., Baldwin, T. A., and Jameson, S. C. (2005) Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 5, 772–782.
Haller, G. W., Esnaola, N., Yamada, K., et al. (1999) Thymic transplantation across an MHC class I barrier in swine. J. Immunol. 163, 3785–3792.
Yamada, K., Shimizu, A., Ierino, F. L., et al. (1999) Thymic transplantation in miniature swine. I. Development and function of the “thymokidney.” Transplantation 68, 1684–1692.
Kuschnaroff, L. M., Overbergh, L., Sefriouni, H., Sobis, H., Vandeputte, M., and Waer, M. (1999) Effect of staphylococcal enterotoxin B injection on the development of experimental autoimmune encephalomyelitis: influence of cytokine and inducible nitric oxide synthase production. J. Neuroimmunol. 99, 157–168.
Naji, A. (1996) Induction of tolerance by intrathymic inoculation of alloantigen. Curr. Opin. Immunol. 8, 704–709.
Freedman, A. R., Zhu, H., Levine, J. D., Kalams, S., and Scadden, D. T. (1996) Generation of human T lymphocytes from bone marrow CD34+ cells in vitro. Nat. Med. 2, 46–51.
McCune, J. M., Namikawa, R., Kaneshima, H., Shultz, L. D., Lieberman, M., and Weissman, I. L. (1988) The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 241, 1632–1639.
Fisher, A. G., Larsson, L., Goff, L. K., Restall, D. E., Happerfield, L., and Merkenschlager, M. (1990) Human thymocyte development in mouse organ cultures. Int. Immunol. 2, 571–578.
Black, J. (1994) Biological performance of tantalum. Clin. Mater. 16, 167–173.
Bobyn, J. D., Stackpool, G. J., Hacking, S. A., Tanzer, M., and Krygier, J. J. (1999) Characteristics of bone ingrowth and interface mechanics of a new porous tantalum biomaterial. J. Bone Joint Surg. Br. 81, 907–914.
Poznansky, M., Evans, R. H., Foxall, R. B., et al. (2000) Efficient generation of human T cells from a tissue-engineered thymic organoid. Nat. Biotechnol. 18, 729–734.
Anderson, G. and Jenkinson, E. J. (2001) Lymphostromal interactions in thymic development and function. Nat. Rev. Immunol. 1, 31–40.
Clark, R. A., Yamanaka, K. L, Bai, M., Dowgiert, R., and Kupper, T. S. (2005) Human skin cells support thymus-independentT cell development. J. Clin. Invest. 115, 3239–3249.
Hiesse, C., Rieu, P., Kriaa, F., et al. (1997) Malignancy after renal transplantation: analysis of incidence and risk factors in 1700 patients followed during a 25-year period. Transplant. Proc. 29, 831–833.
Garlie, N. K., LeFever, A. V., Siebenlist, R. E., Levine, B. L., June, C. H., and Lum, L. G. (1999) T cells coactivated with immobilized anti-CD3 and anti-CD28 as potential immunotherapy for cancer. J. Immunother. 22, 336–345.
Port, F. K., Dykstra, D. M., Merion, R. M., and Wolfe, R. A. (2004) Organ donation and transplantation trends in the USA (2003). Am. J. Transplant. 4, 7–12.
Kappler, J. W., Roehm, N., and Marrack, P. (1987) T cell tolerance by clonal elimination in the thymus. Cell 49, 273–280.
Kappler, J. W., Staerz, U., White, J., and Marrack, P. C. (1988) Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature 332, 35–40.
Sprent, J., Lo, D., Gao, E. K., and Ron, Y. (1988) T cell selection in the thymus. Immunol. Rev. 101, 173–190.
Coutinho, A., Salaun, J., Corbel, C., Bandeira, A., and Le Douarin, N. (1993) The role of thymic epithelium in the establishment of transplantation tolerance. Immunol. Rev. 133, 225–240.
Oluwole, S. F., Chowdhury, N. C., and Fawwaz, R. A. (1993) Induction of donor-specific unresponsiveness to rat cardiac allografts by pretreatment with intrathymic donor MHC class I antigens. Transplantation 55, 1396–1402.
Posselt, A. M., Barker, C. R, Friedman, A. L., and Naji, A. (1992) Prevention of autoimmune diabetes in the BB rat by intrathymic islet transplantation at birth. Science 256, 1321–1324.
Lee, L. A., Gritsch, H. A., Sergio, J. J., et al. (1994) Specific tolerance across a discordant xenogeneic transplantation barrier. Proc. Natl. Acad. Sci. USA 91, 10,864–10,867.
Zhao, Y., Swenson, K., Sergio, J. J., Arn, J. S., Sachs, D. H., and Sykes, M. (1996) Skin graft tolerance across a discordant xenogeneic barrier. Nat. Med. 2, 1211–1216.
Mezrich, J. D., Benjamin, L. C., Sachs, J. A., et al. (2005) Role of the thymus and kidney graft in the maintenance of tolerance to heart grafts in miniature swine. Transplantation 79, 1663–1673.
Nikolic, B., Gardner J. P., Scadden, D. T., Arn, J. S., Sachs, D. H., and Sykes, M. (1999) Normal development in porcine thymus grafts and specific tolerance of human T cells to porcine donor MHC. J. Immunol. 162, 3402–3407.
Ichim, T. E., Zhong, R., and Min, W. P. (2003) Prevention of allograft rejection by in vitro generated tolerogenic dendritic cells. Transpl. Immunol. 11, 295–306.
Steinman, R. M., Hawiger, D., and Nussenzweig, M. C. (2003) Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711.
Khoury, S. J., Gallon, L., Chen, W., et al. (1995) Mechanisms of acquired thymic tolerance in experimental autoimmune encephalomyelitis: thymic dendriticenriched cells induce specific peripheral T cell unresponsiveness in vivo. J. Exp. Med. 182, 357–366.
Bushell, A., Jones, E., Gallimore, A., and Wood, K. (2005) The generation of CD25+ CD4+ regulatory T cells that prevent allograft rejection does not compromise immunity to a viral pathogen. J. Immunol. 174, 3290–3297.
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Vianello, F., Poznansky, M.C. (2007). Generation of a Tissue-Engineered Thymic Organoid. In: Fairchild, P.J. (eds) Immunological Tolerance. Methods in Molecular Biology™, vol 380. Humana Press. https://doi.org/10.1007/978-1-59745-395-0_9
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DOI: https://doi.org/10.1007/978-1-59745-395-0_9
Publisher Name: Humana Press
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