Background: B and T lymphocytes are produced within specialized niches in bone marrow and thymus, respectively. Although much is known about lymphocyte development, less is understood about their interactions with their supportive niches. After completing development they must exit these primary lymphoid organs and travel to secondary lymphoid organs to survey for pathogens. While mechanisms of cell entry to tissues from blood are well studied, less has been understood about how they exit.
Major goals of our work that relate to stem cell biology include defining the molecular cues that guide cell migration and cell-cell interactions in primary and secondary lymphoid organs and that promote the egress of cells from these organs.
On-going Research: Chemokines are secreted chemoattractive proteins that signal via heterotrimeric G-protein coupled receptors (GPCRs). We have demonstrated that several chemokines are expressed in lymphoid organs and function in guiding lymphocyte migration. The chemokine SDF1 (CXCL12) has functions in retaining stem and progenitor cells in the bone marrow and guiding plasma cells back to this site. We are using transgenic and gene knockout experiments in mice to further defining the organizing functions of chemokines and other guidance molecules in primary and secondary lymphoid organs.
Recently, evidence has emerged that the blood lysophospholipid, sphingosine-1-phosphate (S1P), is involved in promoting lymphocyte exit from thymus and secondary lymphoid organs. Like chemokines, S1P signals via GPCRs, and we have found that if lymphocytes lack one of the five known S1P receptors, S1P1, they are unable to leave the thymus or peripheral lymphoid organs. On-going studies, involving molecular, biochemical and genetic approaches, are aimed at defining how this GPCR instructs lymphocytes to exit lymphoid organs. We are also exploring requirements for lymphocyte and stem cell egress from the bone marrow.
Real-Time 2-photon microscopy is being used to define the dynamics of cell migration and stromal cell interactions in intact lymphoid organs. This includes exploration of how cell migration dynamics change as cells move into different niches.
Germinal centers form in lymphoid organs during responses to pathogens and are sites of antibody somatic mutation and affinity maturation. We are studying the cues that organize the germinal center and promote lymphocyte-stromal cell interactions using molecular, genetic and imaging approaches to better define the selection events involved in antibody affinity maturation.