BACH2 orchestrates thymic T cell differentiation and functional programming

The thymus is a highly specialised organ required for T cell development and establishing immunological tolerance. It is tasked with maximising the number of foreign antigens which can be recognised by the T cell receptor (TCR) repertoire in order to protect from infection. Simultaneously, the thymus must ensure self-tolerance by pruning the repertoire of self-reactive cells, diverting these cells towards deletion or a regulatory fate. During thymic T cell development, the fate of thymocytes is guided by signalling via the TCR and occurs during progressive maturation and waves of selection. How cell-extrinsic TCR signalling is translated into cell-intrinsic transcriptional cues to guide differentiation within individual cells has been widely studied but remains incompletely understood. The transcriptional repressor BACH2 has been widely studied in lymphocyte lineage cells, but its role in thymic T cell development has been overlooked. This thesis presents the first in-depth characterisation of BACH2 within T cell development. Expression of BACH2 is induced following positive selection and heterogeneously expressed in single-positive (SP) thymocytes according to TCR signalling strength. BACH2 expression is highest in agonist-signalled cells, where it functions to restrain negative selection. Subsequently, BACH2 supports the induction of quiescence in regulatory T (Treg) precursor cells to ensure the development of a long-lived peripheral Treg cell pool. Inspired by the importance of the BACH2 expression level, the ‘dose’ of BACH2, this work is extending to create a BACH2 dosed expression (BACH2DE) system. Deployment of BACH2DE in solid tumour adoptive cell therapy models supports maintenance of stem-like features in transferred cells without compromising effector functions, thereby leading to greater persistence and augmented anti-tumour efficacy in vivo. Collectively, this work reveals novel roles for BACH2 in thymic selection, highlights the importance of transcription factor dosage and has important implications for understanding immune-mediated diseases and translation of adoptive T cell therapies.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Evans, Alexander

Advisor dc:contributor.advisor

• Roychoudhuri, Rahul

• Thymus

Licence

• https://www.repository.cam.ac.uk/bitstreams/19ae525b-1090-4005-8556-75d89810a518/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.122962

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/392169