Antigen receptor-mediated signaling is the key determinant governing B lymphocyte activation, differentiation or death. Molecules that modulate signals through the B cell receptor (BCR) can thus be instrumental in determining B cell fate. Much attention has been given to intracellular intermediates acting downstream of the BCR. This proposal addresses the biological role of the B cell """"""""co-receptor"""""""" CD19 which, in the appropriate context, can augment BCR-mediated B cell activation and proliferation. The investigator has found that CD19--deficient mice are impaired in B cell lymphopoiesis and in responding to T cell-dependent antigens, and he proposes to determine the molecular basis for these defects in the context of CD19 association with the BCR and the CD19/CD21 (complement receptor 2)/CD81 complexes.
In Aim 1 the role of CD19 in early B cell development will be examined, focusing on developmental checkpoints regulated by pre-BCR or BCR signaling. This involves a comparative analysis of CD19-/- and wildtype mice, which will be refined by the use of pre-BCR mutant mice and immunoglobulin transgenic mice bred onto the CD19 null background. As CD19-/- mice exhibit a severe reduction in B-1 (formerly ly-1) B cells, in Aim 1b they will determine whether this deficiency is mainly attributed to inefficient generation, expansion or maintenance of this important subpopulation of B cells.
Aim 2 addresses the role of CD19 in the recognition of and activation by foreign antigen. It will be determined whether CD19 acts as the signaling moiety of the CD19/CD21/CD81 complex, which is known to synergize with surface immunoglobulin in the co-recognition of opsonized (C3d-bearing) foreign antigen. Immunizations will be accompanied by flow cytometric and immunohistochemical techniques to assess B cell differentiation, migration and survival.
Aim 3 will delineate the dual roles of CD19 as both a member of the CD19/CD21/CD81 complex and also as an elementary component of the BCR. This will be accomplished by complementation of the CD19 null mutation with transgenes encoding modified CD19 molecules which associate exclusively with the BCR or CD19/CD21/CD81 complexes. This genetic approach will assess the relative contribution of CD19 to the function of these crucial signaling complexes in effecting B cell differentiation and antibody production.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041649-02
Application #
2887523
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Quill, Helen R
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Luo, Wei; Mayeux, Jessica; Gutierrez, Toni et al. (2014) A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels. J Immunol 193:909-920
Rickert, Robert C (2013) New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol 13:578-91

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