Humoral immune responses are critical for protection against pathogens and are a cause of pathogenesis in autoimmune and allergic diseases. Despite their importance, fundamental questions remain regarding how antibody responses are mounted. A major focus of this grant has been to characterize the chemokines and related organizer cues in lymphoid organs that facilitate antibody responses. Key findings pertinent to the current proposal have been: identification of lymph node subcapsular sinus (SCS) macrophages as a site of B cell encounter with opsonized antigen;demonstration that B cells function as antigen transport cells;characterization of CXCR4 and CXCR5 as organizers of the germinal center (GC);visualization of cell migration dynamics in the GC;measurement of B cell -T cell contacts at the follicle-T zone boundary and in the GC leading to evidence that GC B cell selection may occur in part through competition for T cell help. Based on these findings we propose to focus the application on the following three specific aims. One, we seek to further assess how SCS macrophages capture antigen and interact with B cells using fluorescence microscopy, flow cytometry and two-photon imaging approaches. In addition, we will identify chemokine requirements for SCS macrophage positioning using gene expression studies and analysis of gene targeted mice. B cell interaction with follicular dendritic cells will also be visualized. Second we aim to characterize cellular events associated with selection of high affinity B cells in the Germinal Center (GC). We will use adoptive transfer approaches with immunoglobulin `knockin'B cells to study the impact on antibody affinity maturation of chemokine receptor deficiencies that disrupt GC B cell positioning. Third, we will examine the role in the GC response of a further G-protein coupled receptor found to be transcriptionally upregulated in GC B cells. These studies should lead to an improved understanding of how B cells encounter antigen and undergo selection, knowledge that has implications for development of improved vaccines and may suggest novel approaches for reducing unwanted responses to autoantigens or allergens. Public Health Relevance: Humoral immune responses are critical for protection against pathogens and are a cause of pathogenesis in autoimmune and allergic diseases. The proposed studies should lead to an improved understanding of how B cells encounter antigen and undergo selection, knowledge that has implications for development of improved vaccines and may suggest novel approaches for reducing unwanted responses to autoantigens or allergens.

Public Health Relevance

Cyster, Jason G Humoral immune responses are critical for protection against pathogens and are a cause of pathogenesis in autoimmune and allergic diseases. The proposed studies should lead to an improved understanding of how B cells encounter antigen and undergo selection, knowledge that has implications for development of improved vaccines and may suggest novel approaches for reducing unwanted responses to autoantigens or allergens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045073-14
Application #
8239541
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Miller, Lara R
Project Start
1999-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
14
Fiscal Year
2012
Total Cost
$286,592
Indirect Cost
$90,572
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
Reboldi, Andrea; Cyster, Jason G (2016) Peyer's patches: organizing B-cell responses at the intestinal frontier. Immunol Rev 271:230-45
Wu, Shuang; Majeed, Sophia R; Evans, Timothy M et al. (2016) Clathrin light chains' role in selective endocytosis influences antibody isotype switching. Proc Natl Acad Sci U S A 113:9816-21
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
Bannard, Oliver; McGowan, Simon J; Ersching, Jonatan et al. (2016) Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses. J Exp Med 213:993-1009
Muppidi, Jagan R; Lu, Erick; Cyster, Jason G (2015) The G protein-coupled receptor P2RY8 and follicular dendritic cells promote germinal center confinement of B cells, whereas S1PR3 can contribute to their dissemination. J Exp Med 212:2213-22
Barnes, Michael J; Li, Chien-Ming; Xu, Ying et al. (2015) The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function. J Exp Med 212:1011-20
Rodda, Lauren B; Bannard, Oliver; Ludewig, Burkhard et al. (2015) Phenotypic and Morphological Properties of Germinal Center Dark Zone Cxcl12-Expressing Reticular Cells. J Immunol 195:4781-91
Muppidi, Jagan R; Schmitz, Roland; Green, Jesse A et al. (2014) Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma. Nature 516:254-8
Wang, Xiaoming; Rodda, Lauren B; Bannard, Oliver et al. (2014) Integrin-mediated interactions between B cells and follicular dendritic cells influence germinal center B cell fitness. J Immunol 192:4601-9
Gray, Elizabeth E; Ramírez-Valle, Francisco; Xu, Ying et al. (2013) Deficiency in IL-17-committed Vγ4(+) γδ T cells in a spontaneous Sox13-mutant CD45.1(+) congenic mouse substrain provides protection from dermatitis. Nat Immunol 14:584-92

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