Title:
Differentiation program of thymic epithelial cells controlling self and non-self discrimination

 

Taishin Akiyama
The Institute of Medical Science, The University of Tokyo

 

Abstract:
Discrimination between self and non-self are essential for selective immune responses against pathogens and immune surveillance against tumor. Therefore, a breakdown of its regulatory mechanism might provoke autoimmune diseases and tumor. Several lines of evidence revealed that epithelial cells in the thymus control self and non-self discrimination of T cells. Especially, epithelial cells localized in thymic medulla (medullary thymic epithelial cells: mTECs) play unique roles by ectopically expressing a wide variety of proteins including tissue-specific proteins such as insulin and tumor-associated proteins such as carcinoembryonic antigen. mTECs directly or indirectly present these antigen peptides to T cells in the thymus, thereby eliminating T cells potentially reactive to self-tissues. As result, mTECs prevent onset of autoimmune diseases and modulate tumor growth. Although the physiological significance of mTECs is relatively clear, differentiation program of mTECs are poorly understood.
We previously reported requirement of TNF family ligand RANKL and CD40L signaling in mTEC development. RANKL/CD40L signaling activates transcription factor NF-kappaB through activation of signal transducers TRAF6 and NIK (Ref. 1 and 2). Moreover, we recently reported that RANKL signaling induces up-regulation of transcription factor Spi-B, which in turns induces osteoprotegerin (OPG), a decoy receptor for RANKL (Ref. 3). We further showed that such negative feed back regulation by RANKL-Spi-B-OPG system fine-tunes mTEC development and enhances tumor immunity.
In this seminar, I would like to discuss our recent findings regarding new embryonic progenitor cells of mTECs and their differentiation mechanisms.

 

References:
1. Akiyama T et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29:423-437 (2008)

2. Akiyama T et al. TNF receptor family signaling in the development and functions of medullary thymic epithelial cells (review). Front Immunol. 3:278 (2012)

3. Akiyama N et al. Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. J Exp Med. 211:2425-2438 (2014)