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On the role of "aire" and "smad4" in thymic development

Jeker, Lukas Thabo. On the role of "aire" and "smad4" in thymic development. 2006, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7674

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Abstract

The thymus is critical for the evolutionary fitness of mammals. It allows the efficient development
of T cells, a highly potent defense system, while restraining the developing T cells to
prevent self-destruction. In contrast to the extensively studied thymocyte development, the
thymic stroma supporting this development has by far been less studied. As a consequence,
a precise understanding of the molecular mechanisms guiding thymic epithelial cell development
is largely lacking. Thymic tolerance induction is a prerequisite for an organism to bear
the tremendously powerful T cells. Failure of tolerance ultimately leads to potentially fatal
self-destruction. Despite this perception, the molecular mechanisms underlying tolerance
induction await to be unraveled.
It is still unresolved how endogenous self-antigens are being physiologically used for the
control of self-tolerance. The phenomenon of ectopic thymic gene expression of peripheral
self-antigens has been described in recent years. Humans lacking a functional Autoimmune
Regulator (AIRE) gene develop a spontaneous, multiorgan autoimmune syndrome termed
Autoimmune Polyendocrinopathy Ectodermal Dystrophy (APECED) Syndrome. Studies in
mice proposed that the transcription factor aire might be critical in regulating ectopic gene
expression, a possible prerequisite for negative selection. The first part of this PhD project
seeked to generate a mouse model of the human APECED syndrome and to establish a
genetic tool enabling direct in vivo manipulation of the rare cells of Aire expressing thymic
medullary epithelial cells (mTEC). The work presented here describes the successful generation
of such a mouse model and discusses the limitations of the created aire-cre mice to
study in vivo tolerance induction by Aire expressing mTECs.
The second part of the thesis is devoted to the role of Smad4 in thymic epithelial cell
development and function. Thymic epithelial cells constitute the most abundant component
of the stroma, form a 3-D meshwork and express soluble and membrane bound molecules
critical for T cell development. In turn, thymocytes deliver signals that control TEC differentiation.
The molecular nature of this lympho-epithelial cross-talk is incompletely understood.
Members of the TGF-β family of signalling molecules (TGF-β, Bmp and Activins) are critical
in embryonic development of many tissues. Signalling of these molecules occurs via
the cytoplasmic second messenger Smad4. To test whether Smad4 plays a role in thymic
organogenesis, we generated mice specifically deficient for Smad4 expression in TECs.
While lack of Smad4 expression allows for the formation of a thymus, mutant embryos and
postnatal mice display a profoundly reduced thymic cellularity. Thymocyte development, appears, however, surprinsingly normal. Nevertheless, peripheral T cell biology is substantially
affected by the thymic epithelial cell specific Smad4 deficiency. A persistent T cell lymphopenia
and a substantial shift in the balance of naive to regulatory T cells are unexpected
results. These striking findings illustrate that the importance of thymic epithelial cells beyond
the thymus knows no bounds.
Advisors:Holländer, Georg A.
Committee Members:Palmer, Ed and Rolink, Antonius G.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Pediatric Immunology (Holländer)
UniBasel Contributors:Palmer, Ed and Rolink, Antonius G.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:7674
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:160
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 15:59

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