The dogma of hematopoiesis states that bone marrow hematopoietic stem cells (HSCs) produce a life time supply of blood and immune cells with limited lifespans and require continuous replenishment. However, antibody producing B cells in unperturbed adult mice are ontogenically distinct with a significant portion being generated within the first weeks of life and self-sustaining throughout adulthood.
Our previous work has demonstrated a critical role for the Lin28b RNA binding protein in mediating a juvenile-to-adult switch in B cell output at the level of hematopoietic stem and progenitor cells (Yuan et al. Science, 2012, Kristiansen et al. Immunity, 2016). Our most recent paper identifies the central tolerance checkpoint as a major target of Lin28b regulation, demonstrating that Lin28b augments the positive selection of self-reactive B cells during a restricted developmental window in the first weeks of life (Vanhee et al. Science Immunology, 2019).
Currently, we are focused on pursuing the molecular, cellular and environmental determinants that control the timing and outcome of this developmental switch as well as its impact on host immunity and disease. By combining several lineage tracing approaches that traces the emergence of immune cells from HSCs across developmental time, with antigen receptor repertoire analyses, well-established immunisation strategies, and cancer models, our work has the following major objectives:
- Peeling back the layers of the adult B cell compartment to resolve the division of labour among ontogenically distinct B cell subsets in health and disease.
- Interrogating early-life molecular, cellular and environmental events responsible for a developmental switch in immune cell output.
Our lineage tracing approach excels at establishing causality between developmental and immunological events disparate in time and space and represents a new way of stratifying the adaptive immune system. Our work addresses important gaps in our knowledge of how nature and nurture shapes the formation of a complex and balanced immune system with important implications in life-long health and the origin of B cell cancers at the extremes of age.
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