The molecular mechanism of cell entry from blood into tissues has been intensely studied over more than three decades. This work has led to a well-defined multistep model of tissue entry by cells and the development of approved therapeutic agents that target entry as a treatment for immunological diseases. Cell egress from tissues into circulation is equally important for immune function yet has been a focus of study for only the last several years. The potential clinical impact of developing agents to modulate cell egress has been highlighted by the September 2010 approval of FTY720 (Fingolimod), a drug that inhibits lymphocyte egress from lymphoid organs, as the first oral treatment for multiple sclerosis. FTY720 is a ligand for four of five sphingosine-1-phosphate (S1P) receptors. T and B cell egress from lymph nodes, spleen and Peyer's patches is dependent on S1P and S1P receptor-1 (S1PR1). This proposal will identify the pathway of B cell egress from the spleen into blood. Secondly, it will characterize how S1PR1 regulates marginal zone B cell movement and antigen transport between subcompartments within the spleen. Thirdly, it will explore the role of a migration- inhibitory S1P receptor, S1PR2, in controlling egress of cells from non-lymphoid tissues into lymph. This work will elucidate key requirements for lymphocyte egress from lymphoid and non-lymphoid tissues, findings that may help in the development of new therapeutics for treatment of autoimmune diseases.
Lymphocyte egress from lymphoid organs is necessary for immune surveillance and for newly activated effector cells to reach sites of infection. This work will identify the pathway of lymphocyte egress from the spleen into blood. Secondly, it will characterize requirements for antigen-transporting B cell movement between compartments within the spleen. Finally, it will define a mechanism regulating cell movement from the skin into lymphatic vessels. The work has the potential of identifying new targets for immunosuppressive drugs and treatment of autoimmune diseases.
|Arnon, Tal I; Horton, Robert M; Grigorova, Irina L et al. (2013) Visualization of splenic marginal zone B-cell shuttling and follicular B-cell egress. Nature 493:684-8|
|Schmidt, Timothy H; Bannard, Oliver; Gray, Elizabeth E et al. (2013) CXCR4 promotes B cell egress from Peyer's patches. J Exp Med 210:1099-107|
|Cyster, Jason G; Schwab, Susan R (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 30:69-94|
|Arnon, Tal I; Xu, Ying; Lo, Charles et al. (2011) GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood. Science 333:1898-903|
|Zikherman, Julie; Jenne, Craig; Watson, Susan et al. (2010) CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development. Immunity 32:342-54|
|Grigorova, Irina L; Panteleev, Mikhail; Cyster, Jason G (2010) Lymph node cortical sinus organization and relationship to lymphocyte egress dynamics and antigen exposure. Proc Natl Acad Sci U S A 107:20447-52|
|Zachariah, Marcus A; Cyster, Jason G (2010) Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328:1129-35|
|Bankovich, Alexander J; Shiow, Lawrence R; Cyster, Jason G (2010) CD69 suppresses sphingosine 1-phosophate receptor-1 (S1P1) function through interaction with membrane helix 4. J Biol Chem 285:22328-37|
|Grigorova, Irina L; Schwab, Susan R; Phan, Tri Giang et al. (2009) Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells. Nat Immunol 10:58-65|
|Jenne, Craig N; Enders, Anselm; Rivera, Richard et al. (2009) T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. J Exp Med 206:2469-81|
Showing the most recent 10 out of 11 publications