Leukocyte Migration and Self-Tolerance Mechanisms in Lymphoid Organs
Major goals: Investigations in this laboratory are focused on defining the molecular cues that guide leukocyte migration in secondary lymphoid organs and the mechanisms that promote lymphocyte egress from primary and secondary lymphoid organs. A parallel line of work examines self-tolerance mechanisms promoting autoreactive B cell elimination within lymphoid organs.
Getting cells together for the immune response: As few as one in 100,000 B and T lymphocytes maybe specific for a single pathogen antigen, such as tetanus toxin, yet these cells must come together if an antibody response is to occur. Bringing antigen-presenting cells and rare antigen-specific B and T lymphocytes into physical contact is a principal function of the spleen, lymph nodes and other secondary lymphoid organs. In the absence of antigen, B and T lymphocytes home to discrete compartments along specific migration routes. During immune responses, dramatic changes in lymphocyte migration take place that favor encounters between antigen reactive B and T cells.
Chemokines as lymphoid tissue organizers: Chemokines are small 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. Transgenic and gene knockout experiments in mice are further defining the organizing functions of these chemokines. Efforts are on-going using microarray, candidate gene and expression cloning approaches to define novel guidance factors involved in promoting cell migration and cell-cell interactions.
Sphingosine-1-phosphate (S1P) and EXIT: A lot is known about how cells get into lymphoid organs, but little is understood about how they get out. Recently, evidence has emerged that the blood lysophospholipid, S1P, is involved. 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.
Real-Time-Imaging: 2-photon microscopy is being used to define the dynamics of lymphocyte migration in intact lymphoid organs. Lymphocytes have been shown to move at a speedy 6-12 um/min and currently we are exploring how cell migration dynamics change as cells encounter antigen or move into different chemokine fields.
Signaling changes in migration: When lymphocytes are stimulated by antigen they exhibit changes in chemokine and S1P responsiveness that help retain the cells in lymphoid organs and promote interactions between rare, antigen-reactive cells. Signaling pathways from antigen receptors that regulate chemokine and S1P responsiveness are being studied.
