The mounting of somatically mutated high affinity antibody responses is important in protection against a range of pathogens and underlies the success of most vaccine strategies. As well as their beneficial functions, GCs are the source of a major class of lymphoma. The interactions between GC B cells and stromal cells in the GC niche that support events necessary for GC B cell selection and survival are incompletely understood as are the mechanisms promoting GC B cell growth regulation and confinement. The research proposed in this application will advance knowledge in both of these areas. First, the properties of a newly identified stromal cell type, termed CXCL12-expressing reticular cells (CRCs), present within GCs will be investigated. The phenotype and developmental requirements of CRCs will be studied, the dynamics of GC B cell interaction with this new component of the GC niche tracked using intravital 2-photon microscopy, and the functional roles of the cells will be probed. Their role in positioning CXCR4-expressing follicular helper T cells, as well as GC B cells, will be investigated. Second, the mechanism of G?13-mediated regulation of GC B cell growth and migration will be dissected. One receptor-ligand interaction important for transmitting G?13- signals that control GC B cell growth and confinement is that between the lysophospholipid sphingosine-1-phosphate (S1P) and its receptor S1PR2. Both G?13and S1PR2 are frequently mutated in human GC B cell-type diffuse large B cell lymphoma (GCB-DLBCL) and loss of either gene is sufficient to predispose mice to this malignancy. Although GC B cells are non-recirculatory, GCB-DLBCL presents as a systemic disease. Preliminary data show that G?13-deficiency in mice is sufficient to cause a loss of GC B cell confinement and allow GC B cells to enter circulation. S1PR2-deficiency, however, does not lead to GC B cell dissemination. These observations have led to the discovery that an orphan G-protein coupled receptor (GPCR) that is frequently mutated in GCB-DLBCL, P2RY8, also promotes GC B cell growth regulation and confinement by engaging G?13. A major goal of this proposal is to define the expression and function of this novel human GPCR, and the mechanism of G?13-mediated GC B cell confinement in GCs. Mounting appropriately regulated immune responses is essential for human health. This work will define how a new stromal cell type supports GC B cell somatic mutation and selection events necessary for generating highly mutated antibodies such as those capable of mediating broadly neutralizing responses against influenza and HIV-1 antigens. The research will build from evidence that S1PR2 and G?13function in a tumor suppressor and dissemination-inhibitory pathway in GCB-DLBCL to define the role of a new receptor, P2RY8, in this process. These studies are anticipated to have implications for development of new treatment strategies for this malignancy.

Public Health Relevance

B cell responses in germinal centers are critical for protection against pathogens, are a cause of pathogenesis in autoimmune diseases, and their dysregulation underlies common B cell lymphomas. The proposed studies should lead to an improved understanding of how selection of high affinity B cells occurs in germinal centers and how these responses are kept in check, knowledge that has implications for development of improved vaccines and may suggest novel approaches for reducing unwanted responses to autoantigens or allergens. The work has the potential to lead to new treatment strategies for germinal center-type diffuse large B cell lymphoma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI045073-16A1
Application #
8814857
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
1999-04-01
Project End
2019-08-31
Budget Start
2014-09-17
Budget End
2015-08-31
Support Year
16
Fiscal Year
2014
Total Cost
$355,688
Indirect Cost
$130,688
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
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Muppidi, Jagan R; Schmitz, Roland; Green, Jesse A et al. (2014) Loss of signalling via G?13 in germinal centre B-cell-derived lymphoma. Nature 516:254-8
Gray, Elizabeth E; Ramirez-Valle, Francisco; Xu, Ying et al. (2013) Deficiency in IL-17-committed Výý4(+) ýýýý T cells in a spontaneous Sox13-mutant CD45.1(+) congenic mouse substrain provides protection from dermatitis. Nat Immunol 14:584-92
Bannard, Oliver; Horton, Robert M; Allen, Christopher D C et al. (2013) Germinal center centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection. Immunity 39:912-24
Green, Jesse A; Cyster, Jason G (2012) S1PR2 links germinal center confinement and growth regulation. Immunol Rev 247:36-51
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Muppidi, Jagan R; Arnon, Tal I; Bronevetsky, Yelena et al. (2011) Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone. J Exp Med 208:1941-8
Green, Jesse A; Suzuki, Kazuhiro; Cho, Bryan et al. (2011) The sphingosine 1-phosphate receptor S1P? maintains the homeostasis of germinal center B cells and promotes niche confinement. Nat Immunol 12:672-80
Gray, Elizabeth E; Suzuki, Kazuhiro; Cyster, Jason G (2011) Cutting edge: Identification of a motile IL-17-producing gammadelta T cell population in the dermis. J Immunol 186:6091-5
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

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