Mechanisms of CD4+ Regulatory T Cell Heterogeneity in Health and Disease

Regulatory T (Treg) cells are central to the maintenance of immune homeostasis and their dysfunction underlies the pathology of numerous diseases. Treg cell populations are phenotypically heterogeneous, comprising functionally quiescent resting Treg (rTreg) cells, which upon antigen stimulation, differentiate into functionally activated Treg (aTreg) cells. The purpose of rTreg cell populations and how their naïve-like phenotype is maintained despite chronic exposure to cognate self- and foreign antigens remains to be understood. The transcription factor BACH2 is critical for early Treg cell lineage specification, however, its function following Treg lineage-commitment is unresolved. The studies detailed herein demonstrate that Bach2 is highly expressed during Treg cell development in the thymus. High levels of Bach2 are maintained in post-thymic, lineage-committed rTreg cells but is downregulated in aTreg cells, and upon inflammation. Functionally, BACH2 acts to restrain T cell receptor (TCR)-driven activation in rTreg cells and constrain their differentiation into aTreg cells. Cell-autonomous expression of BACH2 is required following Treg cell lineage-commitment for functional quiescence and long-term maintenance of Treg cell populations. This is necessary for the restraint of excessive memory differentiation and IFN-γ production by CD8+ T cells. Therefore, in lineage-committed Treg cells, BACH2-mediated restraint of aTreg cell differentiation is required for the maintenance of immune homeostasis. These findings deepen our understanding of Treg cell biology and extend our knowledge of the function of the transcription factor BACH2 in lymphocytes.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Grant, Francis Matthew

Advisor dc:contributor.advisor

• Roychoudhuri, Rahul

• T cell
• immunosuppression
• autoimmune disease
• cancer
• immunology
• regulatory T cell
• transcription factor

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/af1053ad-241e-4e22-86e2-df6fbcc5b7f7/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.46516

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/299447