Investigating the intrathymic and post-thymic processes which instruct thymic CD25\(^+\)Foxp3\(^+\) regulatory T-cell development

Inglesfield, Sarah Elizabeth ORCID: 0000-0002-3511-9090 (2022). Investigating the intrathymic and post-thymic processes which instruct thymic CD25\(^+\)Foxp3\(^+\) regulatory T-cell development. University of Birmingham. Ph.D.

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Abstract

The thymus is a key site of Treg development, however uncertainty remains regarding how intrathymic and post-thymic processes may contribute to the generation of a diverse peripheral Treg population. Therefore, we used the Rag-GFPxFoxp3-RFP mouse to characterise the development of newly produced Tregs in the thymus and periphery.

Our analysis identified that de novo thymic Tregs contained heterogeneous CD62L\(^{hi}\) and CD62L\(^{lo}\) subsets, generated through a post selection pathway, where some CD62L\(^{hi}\) Tregs differentiated into CD62L\(^{lo}\) Tregs, possibly mediated by interactions with mTEC\(^{hi}\). Both Treg subsets appeared to undergo thymic egress, contributing to the peripheral pool from the earliest neonatal stages. We also identified post-selection proliferation of thymic Tregs, which was most prevalent within the neonate, where it correlated with the large expansion of the earliest thymic Treg population. Further analysis of neonatal thymic Tregs identified they proliferated more extensively than Tconvs, possibly in response to IL-2 and IL-15 signalling. Finally, we performed RNAseq analysis of recent thymic emigrants and their mature counterparts within Treg and Tconv lineages. This comparison identified that both lineages may undergo a modest post-thymic maturation upon egress, featuring some shared elements.

Collectively our findings highlight underappreciated processes involved in intrathymic and post-thymic Treg development.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Anderson, Graham UNSPECIFIED UNSPECIFIED Jenkinson, William UNSPECIFIED UNSPECIFIED Watson, Steve P. UNSPECIFIED UNSPECIFIED Jabbari, Sara UNSPECIFIED UNSPECIFIED
Licence:	All rights reserved
College/Faculty:	Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department:	Institute of Immunology and Immunotherapy
Funders:	Wellcome Trust
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QR Microbiology > QR180 Immunology
URI:	http://etheses.bham.ac.uk/id/eprint/12533

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