Virus infection triggers the proliferation and differentiation of naïve, quiescent CD8+ T cells, resulting in a large pool of effector cells that are now capable of killing infected host cells. Importantly, infection gives rise to a long-lived pool of virus-specific (memory) T cells that reactivate rapidly following re-infection, providing the basis of T cell-mediated immunity. While it is understood that T cell differentiation is orchestrated by global changes in gene transcription, the mechanisms that result in these changes are still largely unknown.
Global changes in the nuclear architecture occur following T cell activation, with modulated deposition of histone modifications and locus-specific regulatory interactions acting to fine-tune gene transcription. At a broader level, the positioning of genes within the nucleus is regulated to influence expression, by altering their proximity to the transcriptional machinery, while higher-order chromatin structures have a less well characterised role to play in imparting cell-type specific transcription profiles. Moreover, how these different layers of regulation work together to choreograph differentiation outcomes is a question that has only recently begun to be addressed.
We are employing single-molecule localisation methods, such as stochastic optical reconstruction microscopy (STORM) combined with genomics techniques to determine how higher order chromatin structures are modulated to regulate T cell differentiation, and how these structural changes control gene transcription to facilitate anti-viral immunity. Ultimately, we will determine how the nucleus is reconfigured to regulate T cell differentiation.