Abstract

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.

Public Health Relevance

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074847-07
Application #
8462890
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Miller, Lara R
Project Start
2007-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$363,075
Indirect Cost
$128,075

  Institution

Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Barnes, Michael J; Cyster, Jason G (2018) Lysophosphatidylserine suppression of T-cell activation via GPR174 requires G?s proteins. Immunol Cell Biol 96:439-445
Zhang, Yang; Roth, Theodore L; Gray, Elizabeth E et al. (2016) Migratory and adhesive cues controlling innate-like lymphocyte surveillance of the pathogen-exposed surface of the lymph node. Elife 5:
Han, Brenda Yuyuan; Foo, Chuan-Sheng; Wu, Shuang et al. (2016) The C2H2-ZF transcription factor Zfp335 recognizes two consensus motifs using separate zinc finger arrays. Genes Dev 30:1509-14
Reboldi, Andrea; Arnon, Tal I; Rodda, Lauren B et al. (2016) IgA production requires B cell interaction with subepithelial dendritic cells in Peyer's patches. Science 352:aaf4822
Ramírez-Valle, Francisco; Gray, Elizabeth E; Cyster, Jason G (2015) Inflammation induces dermal V?4+ ??T17 memory-like cells that travel to distant skin and accelerate secondary IL-17-driven responses. Proc Natl Acad Sci U S A 112:8046-51
Han, Brenda Y; Wu, Shuang; Foo, Chuan-Sheng et al. (2014) Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment. Elife 3:
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
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
Daley, Stephen R; Coakley, Kristen M; Hu, Daniel Y et al. (2013) Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios? T cells and autoantibodies. Elife 2:e01020
Cyster, Jason G; Schwab, Susan R (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 30:69-94

Showing the most recent 10 out of 18 publications