Investigating the role of transcription factor networks in T cell immunoregulatory fate decisions

Regulatory T cells expressing the FoxP3 transcription factor (Tregs) are arguably the most important naturally-occurring anti-inflammatory cells in the body and are prime candidates for cellular therapy of autoimmunity and transplant rejection. They are potently immunosuppressive, indispensable for maintaining self-tolerance and in resolving inflammation. Tregs can be induced to develop dichotomously from naïve precursors that also have the ability to differentiate into inflammatory T cell lineages. The choice of differentiation pathway (“fate decisions”) is directed by environmental signals and interplay between many transcription factors working within networks. The expression of many genes is required for a healthy immune response and this is highlighted by the discovery of many gene mutations that are associated with very early onset auto-immune disease.

Our goal is to understand how transcriptional signals from the environment are integrated in T cells to determine inflammatory versus regulatory T cell differentiation and the quality and duration of effector function. Experimental approaches will involve genomics of patients with primary immuno-deficiencies and very early onset colitis, next generation sequencing platforms (RNA-seq, ChIP-seq, Cut&Run, ATAC-seq, scRNAseq), molecular and cell biology, CRISPR genome editing and in vivo murine models.