Regulation of CD4\(^+\) T cell Il10 transcription and TCR signal strength in tolerance and cancer

Lecky, David Arthur John ORCID: 0000-0002-9333-5605 (2025). Regulation of CD4\(^+\) T cell Il10 transcription and TCR signal strength in tolerance and cancer. University of Birmingham. Ph.D.

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Abstract

T cells secrete IFNγ, which has a key role in activating macrophages and enhancing antigen presentation through increasing MHC class I and II expression. The inflammatory response is counteracted by negative regulators of the immune system, which limit damage to self by excessive immune responses, including via FOXP3\(^+\) CD4\(^+\) Tregs and Type 1 Regulatory CD4\(^+\) T cells (Tr1 cells). These induce negative regulation through PD-1, CTLA-4 and TIGIT, for example, but also through expression of immunosuppressive cytokines such as interleukin-10.

Previously published data showed that immunisation with modified myelin basic protein ([4Y]-MBP) peptide to transgenic Tg4 T cell Receptor (TCR) mice that specifically and uniquely recognise MBP led to rapid induction of \(Il10\) transcription in a CD4\(^+\) T cell subset. Here we sought to define and modulate \(Il10^+\) T cell early development.

We found that a high dose of [4Y]-MBP peptide rapidly induced a Tr1-like phenotype in \(Il10\) expressing CD4\(^+\) T cells, and that emergence of Tr1-like cells was preceded by Ifng transcription. Via APCs, anti-IFNγ strongly reduced CD4\(^+\) Il10 transcription, strong TCR signalling, and Tr1-like markers, an effect that was additive with anti-IL-27. In complementary experiments, we explored the role of IFNγ in modulating T cell \(Il10\) transcription during an anti-tumour immune response. Anti-IFNγ increased tumour burden in mice, reducing their survival, which was associated with reduced CD4\(^+\) T cell \(Il10\) transcription and TCR signalling strength. Changes in \(FoxP3^+\) Treg \(Il10\) transcription through IFNγ neutralisation correlated with reduced activation of tumour associated macrophages. These data reveal a regulatory feedback role for IFNγ and TCR signalling strength in modulating Il10 transcription in two distinct subsets of regulatory T cells under a variety of immune environments.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):