Contrasting models of promiscuous gene expression by thymic epithelium - PubMed (original) (raw)

Review

Contrasting models of promiscuous gene expression by thymic epithelium

Geoffrey O Gillard et al. J Exp Med. 2005.

Abstract

Medullary thymic epithelial cells (mTECs) express a broad spectrum of tissue- restricted self-antigens (TRAs), which are required for the development of central tolerance. A new study suggests that TRA expression is a specialized property of terminally differentiated mTECs. However, as discussed here, an alternative model-whereby TRA expression is regulated by conserved developmental programs active in developing mTECs-may be equally plausible.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

Models of the mechanisms resulting in TRA expression by mTECs. (A) The terminal differentiation model. As a committed mTEC progenitor (p) cell differentiates, it progressively expresses an increasing number of TRAs, starting at an immature (im) stage and culminating in a terminally differentiated (mature [m]) cell that is characterized by high level expression of MHC class II, CD80, Aire, and a broad spectrum of TRAs (represented by colored circles). The role of Aire in this model is undefined but is progressively manifested during mTEC maturation. (B) The developmental model. Progenitors have access to a wide variety of lineage-specific transcriptional programs (and the TRAs regulated by those programs) before differentiation. As part of the differentiation process, some of the transcriptional networks are silenced as individual cells mature. Each of these mature cells might express a peripheral lineage program (i and iii), or might extinguish all peripheral regulators and express an undefined terminal mTEC program (ii). In the developmental model, MHC class II and costimulatory molecules like CD80 would be inducibly expressed on mTECs throughout differentiation in response to cell–cell or other extrinsic signals. We speculate that Aire acts at early stages of mTEC differentiation, perhaps by regulating lineage decisions or by controlling temporal patterns of the differentiation process.

Comment on

References

    1. Kyewski, B., and J. Derbinski. 2004. Self-representation in the thymus: an extended view. Nat. Rev. Immunol. 4:688–698. - PubMed
    1. Smith, K.M., D.C. Olson, R. Hirose, and D. Hanahan. 1997. Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance. Int. Immunol. 9:1355–1365. - PubMed
    1. Klein, L., T. Klein, U. Ruther, and B. Kyewski. 1998. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J. Exp. Med. 188:5–16. - PMC - PubMed
    1. Klein, L., M. Klugmann, K.A. Nave, V.K. Tuohy, and B. Kyewski. 2000. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6:56–61. - PubMed
    1. Derbinski, J., A. Schulte, B. Kyewski, and L. Klein. 2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2:1032–1039. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources