Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 308 (5719): 248-251

Copyright © 2005 by the American Association for the Advancement of Science

Dependence of Self-Tolerance on TRAF6-Directed Development of Thymic Stroma

Taishin Akiyama,1 Shiori Maeda,1 Sayaka Yamane,1 Kaori Ogino,1 Michiyuki Kasai,2 Fumiko Kajiura,3 Mitsuru Matsumoto,3 Jun-ichiro Inoue1*

Abstract: The microenvironments of the thymus are generated by thymic epithelial cells (TECs) and are essential for inducing immune self-tolerance or developing T cells. However, the molecular mechanisms that underlie the differentiation of TECs and thymic compartmentalization are not fully understood. Here we show that deficiency in the tumor necrosis factor receptor–associated factor (TRAF) 6 results in disorganized distribution of medullary TECs (mTECs) and the absence of mature mTECs. Engraftment of thymic stroma of TRAF6-/- embryos into athymic nude mice induced autoimmunity. Thus, TRAF6 directs the development of thymic stroma and represents a critical point of regulation for self-tolerance and autoimmunity.

1 Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108–8639, Japan.
2 Division of Bacterial and Blood Products, National Institute of Infectious Disease, Gakuen, Musashimurayama-shi, Tokyo 208–0011, Japan.
3 Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Kuramoto, Tokushima 770–8503, Japan.

* To whom correspondence should be addressed. E-mail: jun-i{at}ims.u-tokyo.ac.jp


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Thymic Medullary Epithelium and Thymocyte Self-Tolerance Require Cooperation between CD28-CD80/86 and CD40-CD40L Costimulatory Pathways.
J. A. Williams, J. Zhang, H. Jeon, T. Nitta, I. Ohigashi, D. Klug, M. J. Kruhlak, B. Choudhury, S. O. Sharrow, L. Granger, et al. (2014)
J. Immunol. 192, 630-640
   Abstract »    Full Text »    PDF »
Ubiquitin in the immune system.
J. Zinngrebe, A. Montinaro, N. Peltzer, and H. Walczak (2014)
EMBO Rep. 15, 28-45
   Abstract »    Full Text »    PDF »
TRAF3 enforces the requirement for T cell cross-talk in thymic medullary epithelial development.
S. R. Jenkinson, J. A. Williams, H. Jeon, J. Zhang, T. Nitta, I. Ohigashi, M. Kruhlak, S. Zuklys, S. Sharrow, A. Adams, et al. (2013)
PNAS 110, 21107-21112
   Abstract »    Full Text »    PDF »
Phosphatase Wip1 Is Essential for the Maturation and Homeostasis of Medullary Thymic Epithelial Cells in Mice.
L. Sun, H. Li, H. Luo, L. Zhang, X. Hu, T. Yang, C. Sun, H. Chen, L. Zhang, and Y. Zhao (2013)
J. Immunol. 191, 3210-3220
   Abstract »    Full Text »    PDF »
IRF7-Dependent IFN-{beta} Production in Response to RANKL Promotes Medullary Thymic Epithelial Cell Development.
D. C. Otero, D. P. Baker, and M. David (2013)
J. Immunol. 190, 3289-3298
   Abstract »    Full Text »    PDF »
T-Cell Tolerance: Central and Peripheral.
Y. Xing and K. A. Hogquist (2012)
Cold Spring Harb Perspect Biol 4, a006957
   Abstract »    Full Text »    PDF »
Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma.
Y. Mouri, M. Yano, M. Shinzawa, Y. Shimo, F. Hirota, Y. Nishikawa, T. Nii, H. Kiyonari, T. Abe, H. Uehara, et al. (2011)
J. Immunol. 186, 5047-5057
   Abstract »    Full Text »    PDF »
Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin.
N. M. Danzl, L. T. Donlin, and K. Alexandropoulos (2010)
J. Exp. Med. 207, 999-1013
   Abstract »    Full Text »    PDF »
TRAF-Interacting Protein with a Forkhead-Associated Domain B (TIFAB) Is a Negative Regulator of the TRAF6-Induced Cellular Functions.
T. Matsumura, J. Kawamura-Tsuzuku, T. Yamamoto, K. Semba, and J.-i. Inoue (2009)
J. Biochem. 146, 375-381
   Abstract »    Full Text »    PDF »
Checkpoints in the Development of Thymic Cortical Epithelial Cells.
S. Shakib, G. E. Desanti, W. E. Jenkinson, S. M. Parnell, E. J. Jenkinson, and G. Anderson (2009)
J. Immunol. 182, 130-137
   Abstract »    Full Text »    PDF »
Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla.
T. M. McCaughtry, T. A. Baldwin, M. S. Wilken, and K. A. Hogquist (2008)
J. Exp. Med. 205, 2575-2584
   Abstract »    Full Text »    PDF »
Thymic Emigration: When and How T Cells Leave Home.
M. A. Weinreich and K. A. Hogquist (2008)
J. Immunol. 181, 2265-2270
   Abstract »    Full Text »    PDF »
Abnormal NF-{kappa}B Function Characterizes Human Type 1 Diabetes Dendritic Cells and Monocytes.
Z. U. A. Mollah, S. Pai, C. Moore, B. J. O'Sullivan, M. J. Harrison, J. Peng, K. Phillips, J. B. Prins, J. Cardinal, and R. Thomas (2008)
J. Immunol. 180, 3166-3175
   Abstract »    Full Text »    PDF »
Lymphotoxin {beta} Receptor Is Required for the Migration and Selection of Autoreactive T Cells in Thymic Medulla.
M. Zhu, R. K. Chin, A. V. Tumanov, X. Liu, and Y.-X. Fu (2007)
J. Immunol. 179, 8069-8075
   Abstract »    Full Text »    PDF »
Developmental Stage-Dependent Collaboration between the TNF Receptor-Associated Factor 6 and Lymphotoxin Pathways for B Cell Follicle Organization in Secondary Lymphoid Organs.
J. Qin, H. Konno, D. Ohshima, H. Yanai, H. Motegi, Y. Shimo, F. Hirota, M. Matsumoto, S. Takaki, J.-i. Inoue, et al. (2007)
J. Immunol. 179, 6799-6807
   Abstract »    Full Text »    PDF »
RANK signals from CD4+3 inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla.
S. W. Rossi, M.-Y. Kim, A. Leibbrandt, S. M. Parnell, W. E. Jenkinson, S. H. Glanville, F. M. McConnell, H. S. Scott, J. M. Penninger, E. J. Jenkinson, et al. (2007)
J. Exp. Med. 204, 1267-1272
   Abstract »    Full Text »    PDF »
Regulation of CD8+ T Cell Development by Thymus-Specific Proteasomes.
S. Murata, K. Sasaki, T. Kishimoto, S.-i. Niwa, H. Hayashi, Y. Takahama, and K. Tanaka (2007)
Science 316, 1349-1353
   Abstract »    Full Text »    PDF »
Severe Defect in Thymic Development in an Insertional Mutant Mouse Model.
E. Assarsson, B. J. Chambers, K. Hogstrand, E. Berntman, C. Lundmark, L. Fedorova, S. Imreh, A. Grandien, S. Cardell, B. Rozell, et al. (2007)
J. Immunol. 178, 5018-5027
   Abstract »    Full Text »    PDF »
Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation.
G. O. Gillard, J. Dooley, M. Erickson, L. Peltonen, and A. G. Farr (2007)
J. Immunol. 178, 3007-3015
   Abstract »    Full Text »    PDF »
PDGFR{alpha}-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches.
W. E. Jenkinson, S. W. Rossi, S. M. Parnell, E. J. Jenkinson, and G. Anderson (2007)
Blood 109, 954-960
   Abstract »    Full Text »    PDF »
Thymus Medulla Formation and Central Tolerance Are Restored in IKK{alpha}-/- Mice That Express an IKK{alpha} Transgene in Keratin 5+ Thymic Epithelial Cells.
D. Lomada, B. Liu, L. Coghlan, Y. Hu, and E. R. Richie (2007)
J. Immunol. 178, 829-837
   Abstract »    Full Text »    PDF »
NF-{kappa}B2 Is Required for the Control of Autoimmunity by Regulating the Development of Medullary Thymic Epithelial Cells.
B. Zhang, Z. Wang, J. Ding, P. Peterson, W. T. Gunning, and H.-F. Ding (2006)
J. Biol. Chem. 281, 38617-38624
   Abstract »    Full Text »    PDF »
IL-18 produced by thymic epithelial cells induces development of dendritic cells with CD11b in the fetal thymus.
H. Ito, E. Esashi, T. Akiyama, J.-i. Inoue, and A. Miyajima (2006)
Int. Immunol. 18, 1253-1263
   Abstract »    Full Text »    PDF »
Essential Role of I{kappa}B Kinase {alpha} in Thymic Organogenesis Required for the Establishment of Self-Tolerance.
D. Kinoshita, F. Hirota, T. Kaisho, M. Kasai, K. Izumi, Y. Bando, Y. Mouri, A. Matsushima, S. Niki, H. Han, et al. (2006)
J. Immunol. 176, 3995-4002
   Abstract »    Full Text »    PDF »
Developmental regulation of Foxp3 expression during ontogeny.
J. D. Fontenot, J. L. Dooley, A. G. Farr, and A. Y. Rudensky (2005)
J. Exp. Med. 202, 901-906
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882