The role of the thymic medulla in T cell development and tolerance induction

Cowan, Jennifer (2014). The role of the thymic medulla in T cell development and tolerance induction. University of Birmingham. Ph.D.

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Abstract

The thymus is organised into functionally distinct microenvironments that facilitates development of a diverse and self-tolerant T cell repertoire. Following positive selection, thymocytes undergo chemotactic migration from the cortex to the medulla, a site that mediates negative selection of potentially autoreactive CD4+ and CD8+ single positive (SP) thymocytes. Importantly, current models suggest that the medulla also fosters the continued maturation of SP thymocytes, post-selection. However, the mechanisms of thymic medulla function remain unclear.

Using a novel approach based on chemokine receptor expression, we have mapped stages in the positive selection process, and developed a model to study αβT cell development in the absence of medullary thymic epithelial cells (mTEC), but in the presence of an otherwise intact immune system. We show that mTEC are dispensible for the continued development of newly selected CD4+CD69+ SP thymocytes, yet are essential for the generation of FoxP3+ regulatory T cells and their FoxP3-CD25+ progenitors. In addition, although CCR4 represents a marker of early stage CD4+ SP positive selection, it is dispensable for SP medullary accumulation and intrathymic development.

Collectively these findings highlight differences in the developmental requirements of conventional and regulatory CD4+ T cells, and rule out a role for CCR4 in cortex to medulla migration.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):