PhD defence M. (Manzhi) Zhao

Chronic antigen stimulation drives CD8+ T cells into a dysfunctional state known as exhaustion, which has been documented in a variety of chronic infectious diseases and cancer. Under chronic antigenic stimulation, CD8+ T cells progressively develop exhaustion-related characteristics such as upregulating multiple inhibitory receptors, an ordered loss of the capacity to produce cytokines, a diminishing potential to proliferate and finally an increasing propensity to apoptosis. Epigenetic modifications and transcriptional changes underlie these phenotypic and functional changes. The deepening of our knowledge on CD8+ T cells exhaustion, has revealed different differentiation stages of exhausted T cells, namely, progenitor exhausted T cells and terminally exhausted T cells. Progenitor exhausted T cells still maintain a stem-cell like potential to proliferate, and can further differentiated into terminally exhausted T cells, while terminally exhausted T cells only preserve some cytokine production and cytotoxic capacity. Due to the critical function of CTL in eliminating viral infections and lysing tumors, preventing or reversing T cells exhaustion is becoming a major research goal in the field of infectious diseases and tumor immunology, especially after immune check point blockade therapies have brought enormous benefits to cancer treatment. However, to date, the factors that can reverse or prevent T cells from undergoing exhaustion remain largely unknown. The quest to identify such factors motivated us to embark on a series of studies to search for modulators of T cell exhaustion. In this thesis we first introduce our current knowledge about T cell exhaustion and describe the characteristics, the factors that induce T cells exhaustion, and the T cell exhaustion-related potential clinical applications for treating different types of diseases.

Due to corona, the PhD defences do not take place publicly in the usual way in the Senate Hall or in the Professor Andries Querido Room. The candidates will defend their dissertation either in a small group or online.