Skip to main content

Thank you for visiting 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.

  • Letter
  • Published:

Immunogenicity of induced pluripotent stem cells


Induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, hold great promise for regenerative medicine as the renewable source of autologous cells1,2,3,4,5. Whereas it has been generally assumed that these autologous cells should be immune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not been vigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbred C57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, the allogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients. B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach (ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration. In contrast to B6 ESCs, teratomas formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, the majority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, and apparent tissue damage and regression were observed in a small fraction of teratomas. Global gene expression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequently overexpressed in teratomas derived from EiPSCs, and several such gene products were shown to contribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice. These findings indicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiated from iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients.

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

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Immunogenicity of syngeneic and allogenic ESCs in male B6 mice.
Figure 2: A new episomal approach to generate EiPSCs from B6 MEFs.
Figure 3: Cells derived from B6 EiPSCs can be immunogenic in B6 mice.
Figure 4: Abnormal overexpression of some proteins contributes directly to the immunogenicity of cells derived from B6 EiPSC in B6 mice.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE28573.


  1. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007)

    Article  ADS  CAS  Google Scholar 

  4. Park, I.-H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008)

    Article  ADS  CAS  Google Scholar 

  5. Lowry, W. E. et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc. Natl Acad. Sci. USA 105, 2883–2888 (2008)

    Article  ADS  CAS  Google Scholar 

  6. Dhodapkar, K. M. et al. Natural immunity to pluripotency antigen OCT4 in humans. Proc. Natl Acad. Sci. USA 107, 8718–8723 (2010)

    Article  ADS  CAS  Google Scholar 

  7. Jincho, Y. et al. Generation of genome integration-free induced pluripotent stem cells from fibroblasts of C57BL/6 mice without c-Myc transduction. J. Biol. Chem. 285, 26384–26389 (2010)

    Article  CAS  Google Scholar 

  8. Chen, Y. T. et al. Identification of CT46/HORMAD1, an immunogenic cancer/testis antigen encoding a putative meiosis-related protein. Cancer Immun. 5, 9 (2005)

    PubMed  Google Scholar 

  9. Kont, V. et al. Modulation of Aire regulates the expression of tissue-restricted antigens. Mol. Immunol. 45, 25–33 (2008)

    Article  CAS  Google Scholar 

  10. Guermonprez, P., Valladeau, J., Zitvogel, L., Théry, C. & Amigorena, S. Antigen presentation and T cell stimulation by dendritic cells. Annu. Rev. Immunol. 20, 621–667 (2002)

    Article  CAS  Google Scholar 

  11. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G. & Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science 322, 945–949 (2008)

    Article  ADS  CAS  Google Scholar 

  12. Zhou, H. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381–384 (2009)

    Article  CAS  Google Scholar 

  13. Chin, M. H. et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5, 111–123 (2009)

    Article  CAS  Google Scholar 

  14. Liu, L. et al. Activation of the imprinted Dlk1-Dio3 region correlates with pluripotency levels of mouse stem cells. J. Biol. Chem. 285, 19483–19490 (2010)

    Article  CAS  Google Scholar 

  15. Stadtfeld, M. et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175–181 (2010)

    Article  ADS  CAS  Google Scholar 

  16. Doi, A. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nature Genet. 41, 1350–1353 (2009)

    Article  CAS  Google Scholar 

  17. Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010)

    Article  ADS  CAS  Google Scholar 

  18. Polo, J. M. et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotechnol. 28, 848–855 (2010)

    Article  CAS  Google Scholar 

  19. Lister, R. et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011)

    Article  ADS  CAS  Google Scholar 

  20. Zhao, T. & Xu, Y. p53 and stem cells: new developments and new concerns. Trends Cell Biol. 20, 170–175 (2010)

    Article  CAS  Google Scholar 

  21. Gore, A. et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011)

    Article  ADS  CAS  Google Scholar 

  22. Song, H., Hollstein, M. & Xu, Y. p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nature Cell Biol. 9, 573–580 (2007)

    Article  CAS  Google Scholar 

  23. Song, H., Chung, S.-K. & Xu, Y. Modeling Disease in Human ESCs Using an Efficient BAC-Based Homologous Recombination System. Cell Stem Cell 6, 80–89 (2010)

    Article  CAS  Google Scholar 

Download references


We thank M. Abe, S. Ding and K. Hochedlinger for their generous supply of integration-free mouse iPSCs. We thank N. Shastri for his advice on how to identify antigen-specific T cells. We thank J. Fink and Blue Lake of Xu lab as well as UCSD Cancer Center pathologic core for technical support. This work was supported by a NIH grant and an Early Translational Award from California Institute for Regenerative Medicine to Y.X. (ET-01277).

Author information

Authors and Affiliations



T.Z. and Y.X. designed the experiments, analysed the data and wrote the manuscript. T.Z., Z.-N.Z. and Z.R. executed the experiments under the overall coordination of T.Z.

Corresponding author

Correspondence to Yang Xu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-7 with legends. (PDF 16535 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, T., Zhang, ZN., Rong, Z. et al. Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer