Our group explores how the immune system is replenished throughout life. One major aim is to describe events that occur as hematopoietic stem cells transition to progenitors that are destined to become lymphocytes. To that end, we produced the first evidence that myelo-erythroid progenitors…
more segregate at an early stage from those dedicated to T and B cell lineages. The steady state production of lymphocytes is highly regulated, reflecting the influence of positive and negative signals from the bone marrow microenvironment. Our group showed that these include IL-7, TGF-, interferons, prostaglandins, steroid hormones and Wnts. We have also investigated the basis of cell-cell interactions in bone marrow, implicating a number of adhesion and matrix molecules in blood cell formation. Stem and progenitor cells were long thought to be incapable of self/non-self discrimination. However, we found that they express toll-like receptors (TLR) and use them to directly respond to microbial/viral products. While potentially lifesaving, this mechanism can also be harmful in some circumstances. One current focus is on learning how injured hematopoietic stem cells accumulate with age. Recent findings suggest firm commitment of progenitors to one of the immune cell lineages represents a gradual process rather than a series of binary decisions. Furthermore, some aspects of the process are asynchronous and potentially reversible. While fundamental, these discoveries have implications for immunodeficiency, autoimmune and malignant diseases, as well as the newly emerging field of regenerative medicine.
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