Roads to memory: studying the regulation of lymphocyte stemness by fate mapping of single t and nk cells
Almost two decades ago it was first proposed that immunological memory may depend on stem cell-like mechanisms, enabling individual antigen-specific T and B cells to generate progeny that contains short-lived effectors as well as long-lived memory cells. To test this capacity, I have in the past developed a stringent set of single cell-based approaches, which allowed me to show that single CD8+ and CD4+ T central memory cells harbour the capacity to self-renew and generate a diverse offspring of effector cells, but also, show immense variation in executing these essential functions upon activation.
Thus, even physiological immune responses to infection appear not to harness the full protective potential available in every antigen-specific lymphocyte. To better understand the regulatory principles underlying this single-cell derived variation, in the context of classical T-cell memory, T-cell exhaustion and memory-like NK cell responses, I developed novel fate mapping technologies such as ‘single-cell colour barcoding’ and ‘single-cell RNA barcoding’. I will now integrate these approaches with single-cell RNA sequencing, genetic reporter systems and continuous live-cell imaging, to answer three fundamental questions in immunobiology:
1) Do exhausted T-cell responses to chronic infection and adaptive-like immune responses of NK cells also rely on the stem cell-like potential of individual cells? 2) Do single-cell-derived T and NK cell families enter the memory or memory-like exhausted compartment on a direct road or through de-differentiation, after passing through an early effector state? And 3) how is the development of these T and NK cell families influenced by their founding members’ fundamental cellular properties, such as asymmetric cell-division, quorum sensing and cell-cycle speed? Answering these questions will help to identify new molecular targets and therapeutic strategies to enhance or reinvigorate protective immunity against infection or malignancy.