Transcriptional control of cytotoxic lymphocytes An unexpected journey with Hobit

Viral infections come in all flavours and models. CD8 T cells and Natural Killer cells are cells capable of destroying cells that have been infected by viruses. The main theme of this thesis is how a specific protein called Hobit regulates the function of CD8 T cells and NK cells. In chapter 1 we offer a broad introduction key points about how the human immune system respond to infections, with special focus in the human cytomegalovirus (HCMV) response. We offer insights and parallels on how different cell lineages (CD4, CD8 and NK) are programmed in a similar way upon HCMV infection. In chapter 2 we describe that Hobit is highly expressed in human NK cells and CD8 T cells with a cytotoxic phenotype. We demonstrate that Hobit can work as a transcription factor and that it regulates effector features such as IFN-y production. In chapter 3 we expand our analysis of Hobit, demonstrating that it is also expressed in specific human CD4 T cells that has a cytotoxic phenotype. We also show how Hobit expression increases during primary HCMV infection. In chapter 4 we performed metabolic phenotyping of human CD8 T cells. We describe how CD45+ effector memory cells (EMRA) has a specific metabolic state. EMRA cells have a suppressed metabolic status, with both low glycolysis and oxidative phosphorylation. We also describe that Hobit acts a metabolic suppressor in lymphocytes, and that Hobit affects the survival potential of lymphocytes during cell activation or cytokine deprivation. Chapter 5 is devoted to the impact of Hobit in direct regulation of cytotoxic potential. We describe how specific populations of tissue resident memory cells present in non-lymphoid organs (TRM cells) have a stronger cytotoxic potential than circulating memory cells. Furthermore, we use genetic ablation models to demonstrate that Hobit plays a key role in regulating murine granzyme B production in TRM cells. Chapters 6 and 7 are focused on the role of Hobit in the NK cell lineage. Chapter 6 describes that Hobit is induced in NK cells during development and that it plays a role in human NK cell development. In Chapter 7 we show that Hobit induces the expression of the G protein coupled receptor GPR56. GPR56 suppresses immediate effector functions, restricting the production of inflammatory cytokines and target cell killing.