Abstract
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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Acknowledgements
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.
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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.
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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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DOI: https://doi.org/10.1038/nature10664
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