Investigating the thymus medulla’s control of the post-selection maturation and thymic egress of CD4 and CD8 thymocytes

Moore, Callum (2023). Investigating the thymus medulla’s control of the post-selection maturation and thymic egress of CD4 and CD8 thymocytes. University of Birmingham. Ph.D.

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Abstract

Following thymic selection, thymocytes progress through a controlled maturation as they gain functional maturity before undergoing an ordered egress into the periphery. Whilst this maturation and egress is well defined in conventional CD4+ (cSP4) thymocytes, such definition in conventional CD8+ (cSP8) thymocytes is lacking. Using extensive flow cytometric analysis, we looked to bring the definition of these processes in cSP8 in line with that of cSP4, before using this to explore how they are impacted by structural changes in the thymus following bone marrow transplantation (BMT). Through defining true cSP8 for the first time we were able to compare cSP4 and cSP8 side-by-side and show that both lineages use the conveyor-belt mechanism of maturation and egress. Furthermore, we identified the earliest SP8-committed thymocytes within a subpopulation of double-positive (DP) thymocytes. We utilised analysis of this population to highlight thymic selection as the determining factor is the CD4:CD8 T-cell ratio. Our analysis of BMT mice showed that the failure in mTEC recovery in this model does not disrupt the maturation of cSP4 or cSP8 thymocytes. In addition, we report a failure in recovery in thymic portal endothelial cells (TPEC), that control thymic entry and egress, resulting in an accumulation of mature thymocytes in BMT mice. Finally, we were able to utilise our comprehensive definition of cSP8 thymocyte to isolate and analyse the non-conventional Eomes+ SP8 population, highlighting their difference from the cSP8 population and the importance of removing this population from conventional analysis. Collectively our findings define a new approach to defining cSP8 thymocytes, subsequently highlighting a new role for thymic selection in establishing the CD4:CD8 ratio. Additionally we describe further failures in recovery following BMT, with a loss of TPEC rather than mTEC limiting thymic egress.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):