Two B cell molecules, CD40 and CD80 (formerly B7/BB1), which are neither integrins nor selectins, have been paired to coreceptors found on activated (CD40L) or resting (CD28) T cells. These receptor-ligand pairs are novel in that they engage during the cognate T-B dialogues and allow T cells and B cells to sense the state of their partner's activation and then respond appropriately. These two receptor-ligand pairs intimately link during T cell-dependent B cell maturation. CD40 provides an essential signal to B cells from activated CD4+ T cells. Both CD40L deficient patients with X-linked hyper-IgM syndrome and CD40-deficient mice after antigen stimulation cannot form germinal centers or switch from IgM to other Ig classes or subclasses. The major goals of this proposal are to elucidate the signaling and regulation of the CD40L-CD40 pathway and to define other novel surface molecules on human B lymphocytes which regulate T-cell-dependent B cell maturation.
Our Aims are: 1. To define the signaling pathway by CD40 in B lymphocytes. We have found that crosslinking CD40 rapidly induces the activation of NF-kB. We will use the NF-kB response to define early events in CD40 signaling both upstream and downstream from the activation of NF-kB expression. We will use NF-kB and protein tyrosine kinase (PTK) antisense oligonucleotides to test the hypothesis that CD40-dependent induction of IL-6, rescue of apoptosis or isotype class switching requires NF-kB and/or certain PTK;
Aim 2. To test the hypothesis that germinal center formation and isotype class switching require CD40 expression on non-B cells such as dendritic cells (DC) and follicular dendritic cells (FDC). We will produce a transgenic mouse line expressing mouse CD40 on a kappa promoter/enhancer (CD40-B), i.e., expressing CD40 only in B cells, to test this hypothesis;
Aim 3. To characterize the regulation of the expression of the CD40 ligand (CD40L) in T lymphocytes. We have found that crosslinking the CD28 receptor on T cells strongly induces expression of CD40L mRNA and surface protein. Using a genomic clone of mouse CD40L, we Will sequence and characterize the CD40L promoter region. We will define elements in the CD40L promoter that can be activated by crosslinking CD3 and/or CD28 receptors;
Aim 4. To test the hypothesis that Bgp95 and IPO-3 B cell surface molecules function to regulate T-cell-dependent B cell maturation. Although the CD40L-CD40 interaction is essential for T-cell- dependent B cell activation, other receptors on B lymphocytes may also be important in regulating B cell maturation. We have defined novel glycoproteins on human B cells, Bgp95 and IPO-3 that regulate B cell activation. We will isolate cDNAs encoding Bgp95 and IPO-3 and use the cDNAs to define the expression and function of these molecules. These studies will lead to better understanding of how human B cell activation and maturation is regulated by T cells and will help to identify potential sites for dysregulation in B-cell-associated autoimmune diseases and neoplasms.
| Richards, Sabrina M; Clark, Edward A (2009) BCR-induced superoxide negatively regulates B-cell proliferation and T-cell-independent type 2 Ab responses. Eur J Immunol 39:3395-403 |
| Ma, Daphne Y; Clark, Edward A (2009) The role of CD40 and CD154/CD40L in dendritic cells. Semin Immunol 21:265-72 |
| Watanabe, Chie; Shu, Geraldine L; Zheng, Timothy S et al. (2008) Caspase 6 regulates B cell activation and differentiation into plasma cells. J Immunol 181:6810-9 |
| Richards, Sabrina; Watanabe, Chie; Santos, Lorna et al. (2008) Regulation of B-cell entry into the cell cycle. Immunol Rev 224:183-200 |
| Craxton, Andrew; Draves, Kevin E; Clark, Edward A (2007) Bim regulates BCR-induced entry of B cells into the cell cycle. Eur J Immunol 37:2715-22 |
| Acosta-Rodriguez, Eva V; Craxton, Andrew; Hendricks, Deborah W et al. (2007) BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas-mediated cell death. Eur J Immunol 37:990-1000 |
| Paterson, Jennifer C; Tedoldi, Sara; Craxton, Andrew et al. (2006) The differential expression of LCK and BAFF-receptor and their role in apoptosis in human lymphomas. Haematologica 91:772-80 |
| Graves, Jonathan D; Craxton, Andrew; Clark, Edward A (2004) Modulation and function of caspase pathways in B lymphocytes. Immunol Rev 197:129-46 |
| Craxton, Andrew; Magaletti, Dario; Ryan, Elizabeth J et al. (2003) Macrophage- and dendritic cell--dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF. Blood 101:4464-71 |
| Olson, N Eric; Graves, Jonathan D; Shu, Geraldine L et al. (2003) Caspase activity is required for stimulated B lymphocytes to enter the cell cycle. J Immunol 170:6065-72 |
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