Signals transmitted by the antigen receptor on immature or mature B lymphocytes have a direct impact on subsequent cell migration. During development in the bone marrow, antigen receptor signaling by an immature B cell determines whether the cell is rendered tolerant in the marrow microenvironment or is allowed to exit and join the peripheral lymphocyte pool. A practical requirement for either of these outcomes is that immature B cell antigen specificity dictates response to chemoattractants, adhesion, or both. However, this has not been demonstrated nor the chemoattractants identified that facilitate immature B cell exit from the marrow. Antigen receptor signaling by mature B cells in the spleen also promotes the migration of antigen-activated cells to the microenvironment best suited for the antibody response towards that antigen and progress has been made in identifying the chemoattractants participating in this movement. However, whether diverse antigens promote similar migratory responses is not clear nor do we understand how antigen receptor signaling facilitates changes in chemoattractant responsiveness. Furthermore, given that bona fide pathogens also present ligands recognized by toll-like receptors on mature B cells, how antigen receptor and toll-like receptor signaling together influence migration and antibody response has not been established. In this proposal we outline three experimental aims that explore the functional and mechanistic relationships between antigen receptor and chemoattractant receptor signaling on B lymphocytes and the consequence of this regulation on B cell selection and antibody response. To accomplish these goals we use in vitro models of antigen and chemoattractant receptor signaling and cell adhesion coupled with in vivo mouse models of B cell development, tolerance, and antibody response. In the first specific aim we ask how antigen receptor reactivity alters chemoattractant response and adhesion of immature B cells. These findings are extended in the second aim by assessing whether chemoattractants are able to influence antigen receptor signaling and which chemoattractants contribute to immature B cell exit from the bone marrow. In the last specific aim we investigate how the nature of antigen regulates the chemoattractant response of mature marginal zone B cells and whether this regulation is further influenced by toll-like receptor signaling. Throughout this study we use biochemical and genetic approaches to evaluate the molecular mechanisms by which antigen and chemoattractant receptors regulate each other and the points where these signaling pathways intersect. Together, we anticipate these experiments to define how B cell antigen receptor signaling by B lymphocytes dictates subsequent cell movement and the implications of this regulation on B cell development, selection, and humoral immunity.

Public Health Relevance

The appropriate development and function of B lymphocytes is required for mounting antibody responses to foreign antigens while preventing autoimmunity. Both of these processes, development and function, rely on the ability of B lymphocytes to migrate in response to defined cues. This application studies how B lymphocytes regulate migration during their development and later during an antibody response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052157-10
Application #
8212265
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Miller, Lara R
Project Start
2002-08-01
Project End
2013-05-13
Budget Start
2012-02-01
Budget End
2013-05-13
Support Year
10
Fiscal Year
2012
Total Cost
$377,609
Indirect Cost
$125,013
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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