Chemokines and Lymphoid Tissue Organization and Function

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DESCRIPTION (provided by applicant): 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 Gα13-mediated regulation of GC B cell growth and migration will be dissected. One receptor-ligand interaction important for transmitting Gα13- signals that control GC B cell growth and confinement is that between the lysophospholipid sphingosine-1-phosphate (S1P) and its receptor S1PR2. Both Gα13and 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 Gα13-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 Gα13. A major goal of this proposal is to define the expression and function of this novel human GPCR, and the mechanism of Gα13-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 Gα13function 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.