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.

Response to self antigen imprints regulatory memory in tissues


Immune homeostasis in tissues is achieved through a delicate balance between pathogenic T-cell responses directed at tissue-specific antigens and the ability of the tissue to inhibit these responses. The mechanisms by which tissues and the immune system communicate to establish and maintain immune homeostasis are currently unknown. Clinical evidence suggests that chronic or repeated exposure to self antigen within tissues leads to an attenuation of pathological autoimmune responses, possibly as a means to mitigate inflammatory damage and preserve function. Many human organ-specific autoimmune diseases are characterized by the initial presentation of the disease being the most severe, with subsequent flares being of lesser severity and duration1. In fact, these diseases often spontaneously resolve, despite persistent tissue autoantigen expression2. In the practice of antigen-specific immunotherapy, allergens or self antigens are repeatedly injected in the skin, with a diminution of the inflammatory response occurring after each successive exposure3. Although these findings indicate that tissues acquire the ability to attenuate autoimmune reactions upon repeated responses to antigens, the mechanism by which this occurs is unknown. Here we show that upon expression of self antigen in a peripheral tissue, thymus-derived regulatory T cells (Treg cells) become activated, proliferate and differentiate into more potent suppressors, which mediate resolution of organ-specific autoimmunity in mice. After resolution of the inflammatory response, activated Treg cells are maintained in the target tissue and are primed to attenuate subsequent autoimmune reactions when antigen is re-expressed. Thus, Treg cells function to confer ‘regulatory memory’ to the target tissue. These findings provide a framework for understanding how Treg cells respond when exposed to self antigen in peripheral tissues and offer mechanistic insight into how tissues regulate autoimmunity.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Characterization of K5/TGO/DO11 mice.
Figure 2: K5/TGO/DO11 mice develop autoimmune skin disease that resolves spontaneously.
Figure 3: T reg cells are activated upon induction of peripheral antigen.
Figure 4: Memory T reg cells attenuate skin disease upon re-expression of tissue antigen.


  1. James, W. D. Andrews’ Diseases of the Skin: Clinical Dermatology (Saunders Elsevier, 2006)

    Google Scholar 

  2. Lara-Corrales, I. & Pope, E. Autoimmune blistering diseases in children. Semin. Cutan. Med. Surg. 29, 85–91 (2010)

    CAS  Article  Google Scholar 

  3. Sabatos-Peyton, C. A., Verhagen, J. & Wraith, D. C. Antigen-specific immunotherapy of autoimmune and allergic diseases. Curr. Opin. Immunol. 22, 609–615 (2010)

    CAS  Article  Google Scholar 

  4. Diamond, I., Owolabi, T., Marco, M., Lam, C. & Glick, A. Conditional gene expression in the epidermis of transgenic mice using the tetracycline-regulated transactivators tTA and rTA linked to the keratin 5 promoter. J. Invest. Dermatol. 115, 788–794 (2000)

    CAS  Article  Google Scholar 

  5. Murphy, K. M., Heimberger, A. B. & Loh, D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250, 1720–1723 (1990)

    ADS  CAS  Article  Google Scholar 

  6. Wada, N. et al. Aire-dependent thymic expression of desmoglein 3, the autoantigen in pemphigus vulgaris, and its role in T-cell tolerance. J. Invest. Dermatol. 131, 410–417 (2011)

    CAS  Article  Google Scholar 

  7. Mouquet, H. et al. Expression of pemphigus-autoantigen desmoglein 1 in human thymus. Tissue Antigens 71, 464–470 (2008)

    CAS  Article  Google Scholar 

  8. Gavin, M. A., Clarke, S. R., Negrou, E., Gallegos, A. & Rudensky, A. Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo. Nature Immunol. 3, 33–41 (2002)

    CAS  Article  Google Scholar 

  9. Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005)

    CAS  Article  Google Scholar 

  10. Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008)

    ADS  CAS  Article  Google Scholar 

  11. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009)

    CAS  Article  Google Scholar 

  12. Dudda, J. C., Perdue, N., Bachtanian, E. & Campbell, D. J. Foxp3+ regulatory T cells maintain immune homeostasis in the skin. J. Exp. Med. 205, 1559–1565 (2008)

    CAS  Article  Google Scholar 

  13. Kurtulus, S., Tripathi, P., Opferman, J. T. & Hildeman, D. A. Contracting the “mus cells”—does down-sizing suit us for diving into the memory pool? Immunol. Rev. 236, 54–67 (2010)

    CAS  Article  Google Scholar 

  14. Akbar, A. N., Vukmanovic-Stejic, M., Taams, L. S. & Macallan, D. C. The dynamic co-evolution of memory and regulatory CD4+ T cells in the periphery. Nature Rev. Immunol. 7, 231–237 (2007)

    CAS  Article  Google Scholar 

  15. Saff, R. R., Spanjaard, E. S., Hohlbaum, A. M. & Marshak-Rothstein, A. Activation-induced cell death limits effector function of CD4 tumor-specific T cells. J. Immunol. 172, 6598–6606 (2004)

    CAS  Article  Google Scholar 

  16. Setiady, Y. Y., Coccia, J. A. & Park, P. U. In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti-CD25 monoclonal antibody is mediated by FcγRIII+ phagocytes. Eur. J. Immunol. 40, 780–786 (2010)

    CAS  Article  Google Scholar 

  17. Tenorio, E. P., Fernández, J., Olguín, J. E. & Saavedra, R. Depletion with PC61 mAb before Toxoplasma gondii infection eliminates mainly Tregs in BALB/c mice, but activated cells in C57BL/6J mice. FEMS Immunol. Med. Microbiol. 62, 362–367 (2011)

    CAS  Article  Google Scholar 

Download references


We thank C. Benetiz for assistance with animal husbandry, S. Isakson for genotyping, S.-w. Jiang and M. Lee for cell sorting, and K. Ravid and G. Martin for derivation of TRE-TGO transgenic mice. We thank S. Ziegler, Benaroya Research Institute, for transgenic mice. M.D.R. is supported by a Dermatology Foundation Career Development Award and the UCSF Department of Dermatology. This work was partially funded through NIH grants P01 AI35297, R01 AI73656 and U19 AI56388 (to A.K.A.); NIH grant AR055634 to (A.M.-R.); and the Scleroderma Research Foundation (A.M.-R.). I.K.G. is supported by an Erwin Schroedinger Fellowship from the Austrian Science Fund (FWF), J2997-B13.

Author information

Authors and Affiliations



M.D.R. and I.K.G. contributed equally to this work and designed the studies, performed the experiments and analysed the data. M.D.R. and A.K.A wrote the manuscript. J.S.P. collected and analysed data as well as helped with mouse husbandry. K.L. engineered and derived the TRE-TGO mice in the laboratory of A.M.-R. A.K.A. oversaw all study design and data analysis. A.M.-R. was involved in study design and data analysis. All authors discussed results and commented on the manuscript.

Corresponding author

Correspondence to Abul K. Abbas.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-8 with legends. (PDF 8287 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rosenblum, M., Gratz, I., Paw, J. et al. Response to self antigen imprints regulatory memory in tissues. Nature 480, 538–542 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


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

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