Increased generation of Foxp3+ regulatory T cells by manipulating antigen presentation in the thymus

Jiqiang Lin, Lu Yang, Hernandez Moura Silva, Alissa Trzeciak, Yongwon Choi, Susan R. Schwab, Michael L. Dustin and Juan J. Lafaille ()
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Jiqiang Lin: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA
Lu Yang: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA
Hernandez Moura Silva: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA
Alissa Trzeciak: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA
Yongwon Choi: Institute for Immunology, University of Pennsylvania Perelman School of Medicine
Susan R. Schwab: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA
Michael L. Dustin: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA
Juan J. Lafaille: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Regulatory T-cell (Treg) selection in the thymus is essential to prevent autoimmune diseases. Although important rules for Treg selection have been established, there is controversy regarding the degree of self-reactivity displayed by T-cell receptors expressed by Treg cells. In this study we have developed a model of autoimmune skin inflammation, to determine key parameters in the generation of skin-reactive Treg cells in the thymus (tTreg). tTreg development is predominantly AIRE dependent, with an AIRE-independent component. Without the knowledge of antigen recognized by skin-reactive Treg cells, we are able to enhance skin-specific tTreg cell generation using three approaches. First, we increase medullary thymic epithelial cells by using mice lacking osteoprotegerin or by adding TRANCE (RANKL, Tnfsf11). Second, we inject intrathymically peripheral dendritic cells from skin-draining sites. Finally, we inject skin tissue lysates intrathymically. These findings have implications for enhancing the generation of organ-specific Treg cells in autoimmune diseases.

Date: 2016
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DOI: 10.1038/ncomms10562

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