Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Engineering universal cells that evade immune detection

Abstract

The prospect of transplanting cells and tissues without the risk of immune rejection or the need for powerful immunosuppressive drugs is the ‘holy grail’ of transplantation medicine. Now, with the advent of pluripotent stem cells, CRISPR–Cas9 and other gene-editing technologies, the race to create ‘off-the-shelf’ donor cells that are invisible to the immune system (‘universal cells’) has started. One important approach for creating such cells involves the manipulation of genes required for immune recognition, in particular HLA class I and II proteins. Other approaches leverage knowledge of immune-cloaking strategies used by certain bacteria, viruses, parasites, the fetus and cancer cells to induce tolerance to allogeneic cell-based therapies by modifying cells to express immune-suppressive molecules such as PD-L1 and CTLA4–Ig. Various academic groups as well as biotechnology and pharmaceutical companies are on the verge of bringing these therapies into the clinic.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Examples of disorders that could potentially be treated with different types of universal cells.
Fig. 2: HLA class I and II engineering strategies.
Fig. 3: Players in immune recognition and reactions to allografts.

References

  1. Brent, L. A History of Transplantation Immunology. (Academic Press, San Diego, 1996).

    Google Scholar 

  2. Min, D. I. & Monaco, A. P. Complications associated with immunosuppressive therapy and their management. Pharmacotherapy 11, 119S–125S (1991).

    PubMed  CAS  Google Scholar 

  3. Bix, M. et al. Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature 349, 329–331 (1991).

    PubMed  CAS  Google Scholar 

  4. Liao, N. S., Bix, M., Zijlstra, M., Jaenisch, R. & Raulet, D. MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science 253, 199–202 (1991).

    PubMed  CAS  Google Scholar 

  5. Taylor, C. J. et al. Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 366, 2019–2025 (2005).

    PubMed  Google Scholar 

  6. Taylor, C. J., Peacock, S., Chaudhry, A. N., Bradley, J. A. & Bolton, E. M. Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell 11, 147–152 (2012).

    PubMed  CAS  Google Scholar 

  7. Lanza, R. P., Cibelli, J. & West, M. D. Prospects for the use of nuclear transfer in human transplantation. Nat. Biotechnol. 17, 1171–1174 (1999).

    PubMed  CAS  Google Scholar 

  8. Lanza, R. P., Cibelli, J. & West, M. D. Human therapeutic cloning. Nat. Med. 5, 975–977 (1999).

    PubMed  CAS  Google Scholar 

  9. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    PubMed  CAS  Google Scholar 

  10. Nishikawa, S., Goldstein, R. A. & Nierras, C. R. The promise of human induced pluripotent stem cells for research and therapy. Nat. Rev. Mol. Cell Biol. 9, 725–729 (2008).

    PubMed  CAS  Google Scholar 

  11. Mandai, M. et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. New. Engl. J. Med. 376, 1038–1046 (2017).

    PubMed  CAS  Google Scholar 

  12. Schwartz, S. D. et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379, 713–720 (2012).

    PubMed  CAS  Google Scholar 

  13. Schwartz, S. D. et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet 385, 509–516 (2015).

    PubMed  Google Scholar 

  14. Frantz, S. Embryonic stem cell pioneer Geron exits field, cuts losses. Nat. Biotechnol. 30, 12–13 (2012).

    PubMed  CAS  Google Scholar 

  15. ViaCyte, Inc. Center for beta cell therapy in diabetes and viacyte announce start of European clinical trial of human stem cell-derived implants in type 1 diabetes patients. PR Newswire https://www.prnewswire.com/news-releases/center-for-beta-cell-therapy-in-diabetes-and-viacyte-announce-start-of-european-clinical-trial-of-human-stem-cell-derived-implants-in-type-1-diabetes-patients-300781276.html (2019).

  16. Miller, L. W. Trial of embryonic stem cell–derived cardiac progenitor cells. JACC 71, 439–442 (2018).

    PubMed  Google Scholar 

  17. Cyranoski, D. ‘Reprogrammed’ stem cells implanted into patient with Parkinson’s disease. Nature https://doi.org/10.1038/d41586-018-07407-9 (2018).

  18. Gornalusse, G. G. et al. HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat. Biotechnol. 35, 765–772 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  19. Riolobos, L. et al. HLA engineering of human pluripotent stem cells. Mol. Ther. 21, 1232–1241 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  20. Feng, Q. et al. Scalable generation of universal platelets from human pluripotent stem cells. Stem Cell Reports 3, 817–831 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  21. Lu, P. et al. Generating hypoimmunogenic human embryonic stem cells by the disruption of beta 2-microglobulin. Stem Cell Rev. 9, 806–813 (2013).

    CAS  Google Scholar 

  22. Wang, D., Quan, Y., Yan, Q., Morales, J. E. & Wetsel, R. A. Targeted disruption of the β2-microglobulin gene minimizes the immunogenicity of human embryonic stem cells. Stem Cells Transl. Med. 4, 1234–1245 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Rong, Z. et al. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 14, 121–130 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Ostrander, E. A., Davis, B. W. & Ostrander, G. K. Transmissible tumors: breaking the cancer paradigm. Trends Genet. 32, 1–15 (2016).

    PubMed  CAS  Google Scholar 

  25. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Chao, M. P., Weissman, I. L. & Majeti, R. The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr. Opin. Immunol. 24, 225–232 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  27. Peter, M. E. et al. The role of CD95 and CD95 ligand in cancer. Cell Death Differ. 22, 885–886 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Yang, L., Pang, Y. & Moses, H. L. TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 31, 220–227 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  29. Harding, J. et al. Induction of long-term allogeneic cell acceptance and formation of immune privileged tissue in immunocompentent hosts. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/716571v1 (2019).

  30. Deuse, T. et al. Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat. Biotechnol. 37, 252–258 (2019).

    PubMed  CAS  Google Scholar 

  31. Petersdorf, E. W. Optimal HLA matching in hematopoietic cell transplantation. Curr. Opin. Immunol. 20, 588–593 (2008).

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Zachary, A. A. & Leffell, M. S. HLA mismatching strategies for solid organ transplantation — a balancing act. Front Immunol. 7, 575 (2016).

    PubMed  PubMed Central  Google Scholar 

  33. Zijlstra, M. et al. β2-microglobulin deficient mice lack CD48+ cytolytic T cells. Nature 344, 742–746 (1990).

    PubMed  CAS  Google Scholar 

  34. Koller, B. H., Marrack, P., Kappler, J. W. & Smithies, O. Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. Science 248, 1227–1230 (1990).

    PubMed  CAS  Google Scholar 

  35. Zimmer, J. et al. Clinical and immunological aspects of HLA class I deficiency. QJM 98, 719–727 (2005).

    PubMed  CAS  Google Scholar 

  36. Coffman, T. et al. Improved renal function in mouse kidney allografts lacking MHC class I antigens. J. Immunol. 151, 425–435 (1993).

    PubMed  CAS  Google Scholar 

  37. Li, X. & Faustman, D. Use of donor β2-microglobulin-deficient transgenic mouse liver cells for isografts, allografts, and xenografts. Transplantation 55, 940–946 (1993).

    PubMed  CAS  Google Scholar 

  38. Prange, S., Zucker, P., Jevnikar, A. M. & Singh, B. Transplanted MHC class I-deficient nonobese diabetic mouse islets are protected from autoimmune injury in diabetic nonobese recipients. Transplantation 71, 982–985 (2001).

    PubMed  CAS  Google Scholar 

  39. Qian, S. et al. Impact of donor MHC class I or class II antigen deficiency on first- and second-set rejection of mouse heart or liver allografts. Immunology 88, 124–129 (1996).

    PubMed  PubMed Central  CAS  Google Scholar 

  40. Mattapally, S. et al. Human leukocyte antigen class I and II knockout human induced pluripotent stem cell-derived cells: universal donor for cell therapy. J. Am. Heart Assoc. 7, e010239 (2018).

    PubMed  PubMed Central  Google Scholar 

  41. Deuse, T. et al. Human leukocyte antigen I knockdown human embryonic stem cells induce host ignorance and achieve prolonged xenogeneic survival. Circulation 124, S3–S9 (2011).

    PubMed  Google Scholar 

  42. Heath, W. R. & Carbone, F. R. Cross-presentation in viral immunity and self-tolerance. Nat. Rev. Immunol. 1, 126–134 (2001).

    PubMed  CAS  Google Scholar 

  43. Benichou, G., Yamada, Y., Aoyama, A. & Madsen, J. C. Natural killer cells in rejection and tolerance of solid organ allografts. Curr. Opin. Organ. Transplant. 16, 47–53 (2011).

    PubMed  PubMed Central  CAS  Google Scholar 

  44. Lee, N. et al. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc. Natl Acad Sci. USA 95, 5199–5204 (1998).

    PubMed  CAS  Google Scholar 

  45. Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998).

    PubMed  CAS  Google Scholar 

  46. Navarro, F. et al. The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. Eur. J. Immunol. 29, 277–283 (1999).

    PubMed  CAS  Google Scholar 

  47. Pazmany, L. et al. Protection from natural killer cell-mediated lysis by HLA-G expression on target cells. Science 274, 792–795 (1996).

    PubMed  CAS  Google Scholar 

  48. Gonen-Gross, T. et al. Inhibitory NK receptor recognition of HLA-G: regulation by contact residues and by cell specific expression at the fetal-maternal interface. PLOS ONE 5, e8941 (2010).

    PubMed  PubMed Central  Google Scholar 

  49. Rajagopalan, S. & Long, E. O. A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J. Exp. Med. 189, 1093–1100 (1999).

    PubMed  PubMed Central  CAS  Google Scholar 

  50. Dulberger, C. L. et al. Human leukocyte antigen F presents peptides and regulates immunity through interactions with NK cell receptors. Immunity 46, 1018–1029.e7 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  51. Zhao, H. X. et al. Enhanced immunological tolerance by HLA-G1 from neural progenitor cells (NPCS) derived from human embryonic stem cells (hESCs). Cell Physiol. Biochem. 44, 1435–1444 (2017).

    PubMed  CAS  Google Scholar 

  52. Zhao, L., Teklemariam, T. & Hantash, B. M. Heterelogous expression of mutated HLA-G decreases immunogenicity of human embryonic stem cells and their epidermal derivatives. Stem Cell Res. 13, 342–354 (2014).

    PubMed  CAS  Google Scholar 

  53. Horowitz, A. et al. Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry. Sci. Transl Med. 5, 208ra145 (2013).

    PubMed  PubMed Central  Google Scholar 

  54. Hematti, P. Role of mesenchymal stromal cells in solid organ transplantation. Transplant. Rev. 22, 262–273 (2008).

    Google Scholar 

  55. Sugimoto, T. et al. Differential susceptibility of HLA class II antigens induced by gamma-interferon in human neuroblastoma cell lines. Cancer Res. 49, 1824–1828 (1989).

    PubMed  CAS  Google Scholar 

  56. Soldevila, G. et al. HLA DR, DP, DQ induction in human islet beta cells by the cytokine combination IFN-γ+ TNF-α. Autoimmunity 6, 307–317 (1990).

    PubMed  CAS  Google Scholar 

  57. DeSandro, A., Nagarajan, U. M. & Boss, J. M. The bare lymphocyte syndrome: molecular clues to the transcriptional regulation of major histocompatibility complex class II genes. Am. J. Hum. Genet. 65, 279–286 (1999).

    PubMed  PubMed Central  CAS  Google Scholar 

  58. Chang, C. H., Guerder, S., Hong, S. C., van Ewijk, W. & Flavell, R. A. Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression. Immunity 4, 167–178 (1996).

    PubMed  CAS  Google Scholar 

  59. Colunga, A., Hirata, R. & Russell, D. W. Generation of HLA Class II deficient human embryonic stem cells by AAV mediated knockout of RFXANK. Mol. Ther. 22, S14 (2014).

    Google Scholar 

  60. Chen, H. et al. Functional disruption of human leukocyte antigen II in human embryonic stem cell. Biol. Res. 48, 59 (2015).

    PubMed  PubMed Central  Google Scholar 

  61. Cosgrove, D. et al. Mice lacking MHC class II molecules. Cell 66, 1051–1066 (1991).

    PubMed  CAS  Google Scholar 

  62. Ouederni, M. et al. Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients. Blood 118, 5108–5218 (2011).

    PubMed  CAS  Google Scholar 

  63. Grusby, M. J. et al. Mice lacking major histocompatibility complex class I and class II molecules. Proc. Natl Acad. Sci. USA 90, 3913–3917 (1993).

    PubMed  CAS  Google Scholar 

  64. Kimbrel, E. A. & Lanza, R. Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat. Rev. Drug Discov. 14, 681–692 (2015).

    PubMed  CAS  Google Scholar 

  65. Di Lorenzo, T. P., Peakman, M. & Roep, B. O. Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes. Clin. Exp. Immunol. 148, 1–16 (2007).

    PubMed  PubMed Central  Google Scholar 

  66. Mendell, J. R. et al. Dystrophin immunity in Duchenne’s muscular dystrophy. N. Engl. J. Med. 363, 1429–1437 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  67. Cabrera, T. et al. High frequency of altered HLA class I phenotypes in invasive breast carcinomas. Hum. Immunol. 50, 127–134 (1996).

    PubMed  CAS  Google Scholar 

  68. Koopman, L. A., Corver, W. E., van der Slik, A. R., Giphart, M. J. & Fleuren, G. J. Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer. J. Exp. Med. 191, 961–976 (2000).

    PubMed  PubMed Central  CAS  Google Scholar 

  69. Cabrera, T. et al. High frequency of altered HLA class I phenotypes in laryngeal carcinomas. Hum. Immunol. 61, 499–506 (2000).

    PubMed  CAS  Google Scholar 

  70. He, Y. et al. MHC class II expression in lung cancer. Lung Cancer 112, 75–80 (2017).

    PubMed  Google Scholar 

  71. Heyman, M. et al. Interferon system defects in malignant T-cells. Leukemia 8, 425–434 (1994).

    PubMed  CAS  Google Scholar 

  72. Kaplan, D. H. et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc. Natl Acad. Sci. USA 95, 7556–7561 (1998).

    PubMed  CAS  Google Scholar 

  73. Cabrera, T. et al. High frequency of altered HLA class I phenotypes in invasive colorectal carcinomas. Tissue Antigens 52, 114–123 (1998).

    PubMed  CAS  Google Scholar 

  74. van der Stoep, N., Biesta, P., Quinten, E. & van den Elsen, P. J. Lack of IFN-γ-mediated induction of the class II transactivator (CIITA) through promoter methylation is predominantly found in developmental tumor cell lines. Int. J. Cancer 97, 501–507 (2002).

    PubMed  Google Scholar 

  75. van den Elsen, P. J., Holling, T. M., van der Stoep, N. & Boss, J. M. DNA methylation and expression of major histocompatibility complex class I and class II transactivator genes in human developmental tumor cells and in T cell malignancies. Clin. Immunol. 109, 46–52 (2003).

    PubMed  Google Scholar 

  76. Croce, M. et al. Different levels of control prevent interferon-γ-inducible HLA-class II expression in human neuroblastoma cells. Oncogene 22, 7848–7857 (2003).

    PubMed  CAS  Google Scholar 

  77. Satoh, A. et al. Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-γ-induced HLA-DR expression in colorectal and gastric cancer cells. Oncogene 23, 8876–8886 (2004).

    PubMed  CAS  Google Scholar 

  78. Sucker, A. et al. Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions. Nat. Commun. 8, 15440 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  79. Siddle, H. V. et al. Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer. Proc. Natl Acad. Sci. USA 110, 5103–5108 (2013).

    PubMed  CAS  Google Scholar 

  80. Hsiao, Y. W., Liao, K. W., Hung, S. W. & Chu, R. M. Tumor-infiltrating lymphocyte secretion of IL-6 antagonizes tumor-derived TGF-β1 and restores the lymphokine-activated killing activity. J. Immunol. 172, 1508–1514 (2004).

    PubMed  CAS  Google Scholar 

  81. Blaschitz, A., Hutter, H. & Dohr, G. HLA Class I protein expression in the human placenta. Early Pregnancy 5, 67–69 (2001).

    PubMed  CAS  Google Scholar 

  82. Sasaki, N. & Idica, A. The HLA-matching effect in different cohorts of kidney transplant recipients: 10 years later. Clin. Transpl. 25, 261–282 (2010).

    Google Scholar 

  83. Sasazuki, T. et al. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program. N. Engl. J. Med. 339, 1177–1185 (1998).

    PubMed  CAS  Google Scholar 

  84. Lee, S. J. et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 110, 4576–4583 (2007).

    PubMed  CAS  Google Scholar 

  85. Zorn, E. et al. Minor histocompatibility antigen DBY elicits a coordinated B and T cell response after allogeneic stem cell transplantation. J. Exp. Med. 199, 1133–1142 (2004).

    PubMed  PubMed Central  CAS  Google Scholar 

  86. Perreault, C. et al. Minor histocompatibility antigens. Blood 76, 1269–1280 (1990).

    PubMed  CAS  Google Scholar 

  87. Falkenburg, J. H., van de Corput, L., Marijt, E. W. & Willemze, R. Minor histocompatibility antigens in human stem cell transplantation. Exp. Hematol. 31, 743–751 (2003).

    PubMed  CAS  Google Scholar 

  88. Warren, E. H. et al. Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT. Blood 120, 2796–2806 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  89. Spierings, E. Minor histocompatibility antigens: past, present, and future. Tissue Antigens 84, 374–360 (2014).

    PubMed  Google Scholar 

  90. Pye, R. J. et al. A second transmissible cancer in Tasmanian devils. Proc. Natl Acad. Sci. USA 113, 374–379 (2016).

    PubMed  CAS  Google Scholar 

  91. Stammnitz, M. R. et al. The origins and vulnerabilities of two transmissible cancers in tasmanian devils. Cancer Cell 33, 607–619 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  92. King, A. et al. Surface expression of HLA-C antigen by human extravillous trophoblast. Placenta 21, 376–387 (2000).

    PubMed  CAS  Google Scholar 

  93. Turcotte, S. et al. Tumor MHC class I expression improves the prognostic value of T-cell density in resected colorectal liver metastases. Cancer Immunol. Res. 2, 530–537 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  94. Iwayama, Y. et al. Prognostic value of HLA class I expression in patients with colorectal cancer. World J. Surg. Oncol. 13, 36 (2015).

    PubMed  PubMed Central  Google Scholar 

  95. Goeppert, B. et al. Major histocompatibility complex class I expression impacts on patient survival and type and density of immune cells in biliary tract cancer. Br. J. Cancer 113, 1343–1349 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  96. Pinto, E. M. et al. Prognostic significance of major histocompatibility complex class II expression in pediatric adrenocortical tumors: a St. Jude and Children’s Oncology Group study. Clin. Cancer Res. 22, 6247–6255 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  97. Durrant, L. G. et al. Quantitation of MHC antigen expression on colorectal tumours and its association with tumour progression. Br. J. Cancer 56, 425–432 (1987).

    PubMed  PubMed Central  CAS  Google Scholar 

  98. Oldford, S. A., Robb, J. D., Watson, P. H. & Drover, S. HLA-DRB alleles are differentially expressed by tumor cells in breast carcinoma. Int. J. Cancer 112, 399–406 (2004).

    PubMed  CAS  Google Scholar 

  99. Park, I. A. et al. Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling. PLOS ONE 12, e0182786 (2017).

    PubMed  PubMed Central  Google Scholar 

  100. Lin, C. M. & Gill, R. G. Direct and indirect allograft recognition: pathways dictating graft rejection mechanisms. Curr. Opin. Organ Transplant. 21, 40–44 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  101. Erlebacher, A., Vencato, D., Price, K. A., Zhang, D. & Glimcher, L. H. Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. J. Clin. Invest. 117, 1399–1411 (2007).

    PubMed  PubMed Central  CAS  Google Scholar 

  102. Collins, M. K., Tay, C. S. & Erlebacher, A. Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J. Clin. Invest. 119, 2062–2073 (2009).

    PubMed  PubMed Central  CAS  Google Scholar 

  103. Volchek, M. et al. Lymphatics in the human endometrium disappear during decidualization. Hum. Reprod. 25, 2455–2464 (2010).

    PubMed  Google Scholar 

  104. Kapsenberg, M. L. Dendritic-cell control of pathogen-driven T-cell polarization. Nat. Rev. Immunol. 3, 984–993 (2003).

    PubMed  CAS  Google Scholar 

  105. Moldenhauer, L. M. et al. Cross-presentation of male seminal fluid antigens elicits T cell activation to initiate the female immune response to pregnancy. J. Immunol. 182, 8080–8093 (2009).

    PubMed  CAS  Google Scholar 

  106. Rowe, J. H., Ertelt, J. M., Xin, L. & Way, S. S. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 490, 102–106 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  107. Samstein, R. M., Josefowicz, S. Z., Arvey, A., Treuting, P. M. & Rudensky, A. Y. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150, 29–38 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  108. Aluvihare, V. R., Kallikourdis, M. & Betz, A. G. Regulatory T cells mediate maternal tolerance to the fetus. Nat. Immunol. 5, 266–271 (2004).

    PubMed  CAS  Google Scholar 

  109. Shima, T. et al. Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not late pregnancy in allogeneic mice. J. Reprod. Immunol. 85, 121–129 (2010).

    PubMed  CAS  Google Scholar 

  110. Darrasse-Jeze, G., Klatzmann, D., Charlotte, F., Salomon, B. L. & Cohen, J. L. CD4+CD25+ regulatory/suppressor T cells prevent allogeneic fetus rejection in mice. Immunol. Lett. 102, 106–109 (2006).

    PubMed  Google Scholar 

  111. Kauma, S. W., Huff, T. F., Hayes, N. & Nilkaeo, A. Placental Fas ligand expression is a mechanism for maternal immune tolerance to the fetus. J. Clin. Endocrinol. Metab. 84, 2188–2194 (1999).

    PubMed  CAS  Google Scholar 

  112. Qiu, Q., Yang, M., Tsang, B. K. & Gruslin, A. Fas ligand expression by maternal decidual cells is negatively correlated with the abundance of leukocytes present at the maternal-fetal interface. J. Reprod. Immunol. 65, 121–132 (2005).

    PubMed  CAS  Google Scholar 

  113. Hunt, J. S., Vassmer, D., Ferguson, T. A. & Miller, L. Fas ligand is positioned in mouse uterus and placenta to prevent trafficking of activated leukocytes between the mother and the conceptus. J. Immunol. 158, 4122–4128 (1997).

    PubMed  CAS  Google Scholar 

  114. Guleria, I. et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J. Exp. Med. 202, 231–237 (2005).

    PubMed  PubMed Central  CAS  Google Scholar 

  115. Petroff, M. G. et al. B7 family molecules are favorably positioned at the human maternal-fetal interface. Biol. Reprod 68, 1496–1504 (2003).

    PubMed  CAS  Google Scholar 

  116. Munn, D. H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998).

    PubMed  CAS  Google Scholar 

  117. Honig, A. et al. Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance. J. Reprod. Immunol. 61, 79–86 (2004).

    PubMed  CAS  Google Scholar 

  118. Nancy, P. et al. Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 336, 1317–1321 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  119. Martinez de la Torre, Y. et al. Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6. Proc. Natl Acad. Sci. USA 104, 2319–2324 (2007).

    PubMed  CAS  Google Scholar 

  120. Madigan, J. et al. Chemokine scavenger D6 is expressed by trophoblasts and aids the survival of mouse embryos transferred into allogeneic recipients. J. Immunol. 184, 3202–3212 (2010).

    PubMed  CAS  Google Scholar 

  121. Coulie, P. G., van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).

    PubMed  CAS  Google Scholar 

  122. Dunn, G. P., Koebel, C. M. & Schreiber, R. D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).

    PubMed  CAS  Google Scholar 

  123. Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  124. Spranger, S. Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int. Immunol. 28, 383–391 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  125. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    PubMed  PubMed Central  CAS  Google Scholar 

  126. Gooden, M. J., de Bock, G. H., Leffers, N., Daemen, T. & Nijman, H. W. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br. J. Cancer 105, 93–103 (2011).

    PubMed  PubMed Central  CAS  Google Scholar 

  127. Balachandran, V. P. et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat. Med. 17, 1094–1100 (2011).

    PubMed  PubMed Central  CAS  Google Scholar 

  128. Medema, J. P. et al. Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc. Natl Acad. Sci. USA 98, 11515–11520 (2001).

    PubMed  PubMed Central  CAS  Google Scholar 

  129. Barclay, A. N. & van den Berg, T. K. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu. Rev. Immunol. 32, 25–50 (2014).

    PubMed  CAS  Google Scholar 

  130. Matlung, H. L., Szilagyi, K., Barclay, N. A. & van den Berg, T. K. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol. Rev. 276, 145–164 (2017).

    PubMed  CAS  Google Scholar 

  131. Matozaki, T., Murata, Y., Okazawa, H. & Ohnishi, H. Functions and molecular mechanisms of the CD47-SIRPα signalling pathway. Trends Cell. Biol. 19, 72–80 (2009).

    PubMed  CAS  Google Scholar 

  132. Nathan, C. & Muller, W. A. Putting the brakes on innate immunity: a regulatory role for CD200? Nat. Immunol. 2, 17–19 (2001).

    PubMed  CAS  Google Scholar 

  133. Kretz-Rommel, A. et al. CD200 expression on tumor cells suppresses antitumor immunity: new approaches to cancer immunotherapy. J. Immunol. 178, 5595–5605 (2007).

    PubMed  CAS  Google Scholar 

  134. Siva, A. et al. Immune modulation by melanoma and ovarian tumor cells through expression of the immunosuppressive molecule CD200. Cancer Immunol. Immunother. 57, 987–996 (2008).

    PubMed  CAS  Google Scholar 

  135. Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M. & Swartz, M. A. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749–752 (2010).

    PubMed  CAS  Google Scholar 

  136. Bierie, B. & Moses, H. L. Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer 6, 506–520 (2006).

    PubMed  CAS  Google Scholar 

  137. Flavell, R. A., Sanjabi, S., Wrzesinski, S. H. & Licona-Limon, P. The polarization of immune cells in the tumour environment by TGFβ. Nat. Rev. Immunol. 10, 554–567 (2010).

    PubMed  CAS  Google Scholar 

  138. Belov, K. The role of the major histocompatibility complex in the spread of contagious cancers. Mamm. Genome 22, 83–90 (2011).

    PubMed  CAS  Google Scholar 

  139. Decker, B. et al. Comparison against 186 canid whole-genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor. Genome Res. 25, 1646–1655 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  140. McSorley, H. J. & Maizels, R. M. Helminth infections and host immune regulation. Clin. Microbiol. Rev. 25, 585–608 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  141. Gomez-Munoz, M. T. et al. Inhibition of bovine T lymphocyte responses by extracts of the stomach worm Ostertagia ostertagi. Vet. Parasitol. 120, 199–214 (2004).

    PubMed  CAS  Google Scholar 

  142. Donnelly, S., O’Neill, S. M., Sekiya, M., Mulcahy, G. & Dalton, J. P. Thioredoxin peroxidase secreted by fasciola hepatica induces the alternative activation of macrophages. Infect. Immun. 73, 166–173 (2005).

    PubMed  PubMed Central  CAS  Google Scholar 

  143. Flynn, R. J. & Mulcahy, G. The roles of IL-10 and TGF-β in controlling IL-4 and IFN-γ production during experimental fasciola hepatica infection. Int. J. Parasitol. 38, 1673–1680 (2008).

    PubMed  CAS  Google Scholar 

  144. Layland, L. E. et al. Pronounced phenotype in activated regulatory T cells during a chronic helminth infection. J. Immunol. 184, 713–724 (2010).

    PubMed  CAS  Google Scholar 

  145. Grainger, J. R. et al. Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway. J. Exp. Med. 207, 2331–2341 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  146. Blankenhaus, B. et al. Strongyloides ratti infection induces expansion of Foxp3+ regulatory T cells that interfere with immune response and parasite clearance in BALB/c mice. J. Immunol. 186, 4295–4305 (2011).

    PubMed  CAS  Google Scholar 

  147. Ludwig-Portugall, I. & Layland, L. E. TLRs, Treg, and B cells, an interplay of regulation during helminth infection. Front. Immunol. 3, 8 (2012).

    PubMed  PubMed Central  Google Scholar 

  148. Terrazas, C. A., Terrazas, L. I. & Gomez-Garcia, L. Modulation of dendritic cell responses by parasites: a common strategy to survive. J. Biomed. Biotechnol. 2010, 357106 (2010).

    PubMed  PubMed Central  Google Scholar 

  149. Smyth, D. J. et al. TGF-β mimic proteins form an extended gene family in the murine parasite heligmosomoides polygyrus. Int. J. Parasitol. 48, 379–385 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  150. Johnston, C. J. C. et al. A structurally distinct TGF-β mimic from an intestinal helminth parasite potently induces regulatory T cells. Nat. Commun. 8, 1741 (2017).

    PubMed  PubMed Central  Google Scholar 

  151. Everts, B., Smits, H. H., Hokke, C. H. & Yazdanbakhsh, M. Helminths and dendritic cells: sensing and regulating via pattern recognition receptors, Th2 and Treg responses. Eur. J. Immunol. 40, 1525–1537 (2010).

    PubMed  CAS  Google Scholar 

  152. Robinson, M. W. et al. A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase. FASEB J. 26, 4614–4627 (2012).

    PubMed  CAS  Google Scholar 

  153. Maizels, R. M., Bundy, D. A., Selkirk, M. E., Smith, D. F. & Anderson, R. M. Immunological modulation and evasion by helminth parasites in human populations. Nature 365, 797–805 (1993).

    PubMed  CAS  Google Scholar 

  154. Hewitson, J. P., Grainger, J. R. & Maizels, R. M. Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol. Biochem. Parasitol. 167, 1–11 (2009).

    PubMed  PubMed Central  CAS  Google Scholar 

  155. Liang, Q. et al. Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. Nature 563, 701–704 (2018).

    PubMed  CAS  Google Scholar 

  156. Hicklin, D. J. et al. β2-Microglobulin mutations, HLA class I antigen loss, and tumor progression in melanoma. J. Clin. Invest. 101, 2720–2729 (1998).

    PubMed  PubMed Central  CAS  Google Scholar 

  157. Hanna, S. & Etzioni, A. MHC class I and II deficiencies. J. Allergy Clin. Immunol. 134, 269–275 (2014).

    PubMed  CAS  Google Scholar 

  158. Street, S. E. et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. J. Exp. Med. 199, 879–884 (2004).

    PubMed  PubMed Central  CAS  Google Scholar 

  159. Metzger, M. J. et al. Widespread transmission of independent cancer lineages within multiple bivalve species. Nature 534, 705–709 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  160. Pearse, A. M. & Swift, K. Allograft theory: transmission of devil facial-tumour disease. Nature 439, 549 (2006).

    PubMed  CAS  Google Scholar 

  161. Spriggs, M. K. et al. Beta 2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses. Proc. Natl Acad. Sci. USA 89, 6070–6074 (1992).

    PubMed  CAS  Google Scholar 

  162. Hou, S., Doherty, P. C., Zijlstra, M., Jaenisch, R. & Katz, J. M. Delayed clearance of Sendai virus in mice lacking class I MHC-restricted CD8+ T cells. J. Immunol. 149, 1319–1325 (1992).

    PubMed  CAS  Google Scholar 

  163. Eichelberger, M., Allan, W., Zijlstra, M., Jaenisch, R. & Doherty, P. C. Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J. Exp. Med. 174, 875–880 (1991).

    PubMed  CAS  Google Scholar 

  164. Neal, Z. C. & Splitter, G. A. Protection against lethal encephalomyocarditis virus infection in the absence of serum-neutralizing antibodies. J. Virol. 72, 8052–8060 (1998).

    PubMed  PubMed Central  CAS  Google Scholar 

  165. Bodmer, H., Obert, G., Chan, S., Benoist, C. & Mathis, D. Environmental modulation of the autonomy of cytotoxic T lymphocytes. Eur. J. Immunol. 23, 1649–1654 (1993).

    PubMed  CAS  Google Scholar 

  166. Laufer, T. M., von Herrath, M. G., Grusby, M. J., Oldstone, M. B. & Glimcher, L. H. Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice. J. Exp. Med. 178, 589–596 (1993).

    PubMed  CAS  Google Scholar 

  167. Gargett, T. & Brown, M. P. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front. Pharmacol. 5, 235 (2014).

    PubMed  PubMed Central  Google Scholar 

  168. Atala, A., Lanza, R., Mikos, A. G. & Nerem, R. Principles of Regenerative Medicine 3rd Edition (Academic Press, London/San Diego, 2019).

    Google Scholar 

  169. Lanza, R., Langer, R. & Vacanti, J. Principles of Tissue Engineering 4th Edition (Academic Press, London/San Diego, 2014).

    Google Scholar 

Download references

Acknowledgements

The authors thank J. Harding for his critical and helpful input.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Robert Lanza.

Ethics declarations

Competing interests

R.L., D.W.R. and A.N. are employees and/or founders of the Astellas Institute for Regenerative Medicine, Universal Cells Inc. and panCELLa Inc., respectively, companies in the area of regenerative medicine, including the generation of cell therapies and universal cells.

Additional information

Peer review informationNature Reviews Immunology thanks Sonia Schrepfer, Xang Xu and Rainer Blasczyk for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Intrabody

An antibody that works within cells to bind to a specific intracellular protein.

Cross-presentation

The uptake and presentation of antigens by cells that do not express those antigens themselves.

‘Direct recognition’ pathway

Host T cells can rapidly recognize a donor antigen that is being presented directly by donor antigen-presenting cells that are present during transplant. As opposed to indirect recognition, where host T cells recognize an antigen that is being presented by host antigen-presenting cells, which usually takes more time because the host has to acquire and process donor antigen.

iCasp9

The dimerizing small drug-inducible Caspase 9 system kills cells by initiating apoptosis.

Herpes simplex virus thymidine kinase

A commonly used suicide gene. Cells expressing herpes simplex virus thymidine kinase die in the presence of gancyclovir.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lanza, R., Russell, D.W. & Nagy, A. Engineering universal cells that evade immune detection. Nat Rev Immunol 19, 723–733 (2019). https://doi.org/10.1038/s41577-019-0200-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-019-0200-1

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing