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.
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James, W. D. Andrews’ Diseases of the Skin: Clinical Dermatology (Saunders Elsevier, 2006)
Lara-Corrales, I. & Pope, E. Autoimmune blistering diseases in children. Semin. Cutan. Med. Surg. 29, 85–91 (2010)
Sabatos-Peyton, C. A., Verhagen, J. & Wraith, D. C. Antigen-specific immunotherapy of autoimmune and allergic diseases. Curr. Opin. Immunol. 22, 609–615 (2010)
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)
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)
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)
Mouquet, H. et al. Expression of pemphigus-autoantigen desmoglein 1 in human thymus. Tissue Antigens 71, 464–470 (2008)
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)
Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005)
Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008)
Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009)
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)
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)
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)
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)
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)
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)
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.
The authors declare no competing financial interests.
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Rosenblum, M., Gratz, I., Paw, J. et al. Response to self antigen imprints regulatory memory in tissues. Nature 480, 538–542 (2011). https://doi.org/10.1038/nature10664
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