Understanding the regulators of adaptive tolerance in chronically stimulated CD4+ T-cells.

Done, Reygn (2025). Understanding the regulators of adaptive tolerance in chronically stimulated CD4+ T-cells. University of Birmingham. M.Sc.

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Abstract

Chronic T-cell receptor (TCR) stimulation is a central driver of CD4+ T-cell hyporesponsiveness. During prolonged stimulation, CD4+ T-cells either enter a state of tolerance, mimicking anergy, or differentiate into type-1 regulatory T-cells (Tr1), a distinct FoxP3- regulatory T-cell (Treg) subset crucial for maintaining immune tolerance via IL10 production. The specific regulators of adaptive tolerance, and how they differ from CD8+ T-cell exhaustion, remain unclear. Moreover, the signalling dynamics within Tr1-like cells and their environmental modulation are not well understood yet are of significant therapeutic interest. To study chronic-stimulation induced tolerance, Nur77-Tempo mice received escalation dose immunotherapy, allowing us to analyse NFAT-independent TCR signalling. Our study reveals that chronic stimulation-induced tolerance in CD4+ T-cells is associated with increased immune checkpoint (IC) expression and increased Tr1-like selection. These tolerised T-cells display intrinsic signalling defects in multiple T-cell signalling pathways which can be reversed by combined IC blockade (anti-PD-L1 and anti-Lag3) in-vivo. Importantly, Tr1-like cells remain responsive to chronic antigen exposure and exhibit heightened sensitivity to IC blockade. While the total and responsive Tr1-like cell populations increase following combination therapy, IL10 expression levels remain stable, indicating that ICs may regulate IL10 production within Tr1-like cells. We conclude that shared biological mechanisms underpin different forms of T-cell dysfunction, including tolerance and exhaustion. ICs are pivotal in enforcing tolerance, yet their function evolves following Tr1 differentiation, supporting the maintenance of a tolerogenic state. These findings suggest a need for further research to understand the impact of IC blockade on Tr1-like cells in various disease contexts, including cancer.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):