Genetic and biochemical dissection of quiescence in immune cells
The immune system maintains a vast repertoire of B and T-cells waiting to respond to microbial invasion. These cells are kept in a quiescent state, characterized by arrest in G0 and a decrease in cell size and metabolic activity, until they are activated by antigen engagement and co-stimulation to acquire their effector functions. During the past two decades, numerous types of signaling and changes in gene expression leading to lymphocyte activation, expansion, and acquisition of effector functions have been described. However, the nature and molecular enforcement of quiescence is far from being elucidated. In fact not long ago quiescence was considered equivalent to “absence of activation”, namely a default state of the cell. The factors regulating the quiescence process may have the potential to be exploited for therapeutic purposes in immune diseases, either by enhancing specific anti-pathogen and anti-tumor immune responses or by suppressing overactive, self-directed responses observed in autoimmune diseases, allergy, graft-versus-host disease, and allogeneic transplantation. Fulfillment of this potential is not yet within reach because lymphocyte quiescence is still poorly understood and many issues remain to be addressed. For example: what signals are responsible for maintaining quiescence? And what are the factors that sense those signals, translating them into activation of quiescence-maintaining transcription factors?
The aim of my research is to clarify these crucial questions. We are employing traditional molecular approaches in combination with unbiased functional forward genetic screening to provide comprehensive and integrative insights into the factors and mechanisms that establish and maintain lymphocyte quiescence. In addition, we are exploring ways how to exploit our findings in order to better treat leukemia and improve vaccines