Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

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Ab affinity maturation within germinal centers (GCs) requires weeks to complete. Several signaling pathways in B cells have been shown to be required for initiation of the GC response; however, the signaling checkpoints controlling progression and eventual dissolution of the GC reaction are poorly understood. The adaptor protein Bam32/DAPP1 was originally isolated from human GCs and functions downstream of phosphoinositide 3-kinase enzymes, which are known to have critical roles in B cell activation and GC responses. In this study we identify a unique role of Bam32/DAPP1 in promoting GC progression. Bam32-deficient mice show normal GC initiation, but premature GC dissolution after immunization with protein Ag in alum or low doses of sheep red blood cells. Adoptive transfer studies confirmed that Bam32-deficient B cells have an intrinsic impairment in the ability to mount sustained GC responses. Bam32 deficiency was also associated with impaired Ab affinity maturation. Proliferation of Bam32-deficient GC B cells was not compromised; however, these cells show impaired switch to IgG1 and increased apoptosis in situ. GCs formed by Bam32-deficient B cells contain fewer T cells, indicating that Bam32 is required for B cell–dependent T cell accumulation within established GCs. Exogenous CD40 ligand restored GC B cell numbers and switch to IgG1, indicating that Bam32-deficient B cells are competent to respond to CD40 stimulation when ligand is available. These data demonstrate that Bam32 is not required for GC initiation, but rather functions in a late checkpoint of GC progression associated with T cell recruitment and GC B cell survival.

Section: Discussionsupporting

confidence: 76%

The Pleckstrin Homology Domain Adaptor Protein Bam32/DAPP1 Is Required for Germinal Center Progression

Zhang

Al‐Alwan²,

Marshall

2009

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“…Moreover, the migration of MZ B cells to the pancreatic lymph node, where they present self-Ags to autoreactive T cells, has been implicated in the development of diabetes in NOD mice (59). IC87114 effectively blocks the ability of B cells to present Ags and activate T cells (18). These data, together with our findings that IC87114 reduces both CXCL13-induced MZ B cell migration and TLR-induced Ab production by MZ B cells, suggest that p110␦ inhibitors could reduce the ability of MZ B cells to traffic to other organs and contribute to autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

“…For conventional B-2 cells, activation of the PI3K signaling pathway by chemokine receptors, the BCR, cytokine receptors, and TLRs plays an important role in their development, their trafficking and Ag presentation functions, their activation and proliferation, and their ability to differentiate into Ab-producing cells (17)(18)(19)(20)(21). Although B cells express all four isoforms of the class I PI3K p110 catalytic subunit (22), the p110␦ isoform, which is expressed primarily in hematopoietic cells, appears to be the most important for B cell development and activation.…”

mentioning

confidence: 99%

Phosphoinositide 3-Kinase p110δ Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses

Durand

Hartvigsen²,

Fogelstrand³

et al. 2009

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119

103

B-1 and marginal zone (MZ) B cells produce natural Abs, make Ab responses to microbial pathogens, and contribute to autoimmunity. Although the δ isoform of the PI3K p110 catalytic subunit is essential for development of these innate-like B cells, its role in the localization, activation, and function of normal B-1 and MZ B cells is not known. Using IC87114, a highly selective inhibitor of p110δ enzymatic activity, we show that p110δ is important for murine B-1 and MZ B cells to respond to BCR clustering, the TLR ligands LPS and CpG DNA, and the chemoattractants CXCL13 and sphingosine 1-phosphate. In these innate-like B cells, p110δ activity mediates BCR-, TLR- and chemoattractant-induced activation of the Akt prosurvival kinase, chemoattractant-induced migration, and TLR-induced proliferation. Moreover, we found that TLR-stimulated Ab responses by B-1 and MZ B cells, as well as the localization of MZ B cells in the spleen, depend on p110δ activity. Finally, we show that the in vivo production of natural Abs requires p110δ and that p110δ inhibitors can reduce in vivo autoantibody responses. Thus, targeting p110δ may be a novel approach for regulating innate-like B cells and for treating Ab-mediated autoimmune diseases.

“…We recently found that activity of the p110d isoform of PI3K is required for efficient BCR-mediated Ag presentation (24). PI3K signaling is not required for BCR endocytosis or association with late endosomes but is required for Ag-pulsed B cells to form conjugates with cognate T cells.…”

mentioning

confidence: 99%

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

Al‐Alwan¹,

Hou²,

Zhang

et al. 2010

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B cell Ag receptors function in both signaling activation of Ag-specific cells and in collecting specific Ag for presentation to T lymphocytes. Signaling via PI3K is required for BCR-mediated activation and Ag presentation functions; however, the relevant downstream targets of PI3K in B cells are incompletely defined. In this study, we have investigated the roles of the PI3K effector molecule Bam32/DAPP1 in BCR signaling and BCR-mediated Ag presentation functions. In mouse primary B cells, Bam32 was required for efficient activation of the GTPase Rac1 and downstream signaling to JNK, but not activation of BLNK, phospholipase C γ2, or calcium responses. Consistent with a role of this adaptor in Rac-mediated cytoskeletal rearrangement, Bam32 was required for BCR-induced cell adhesion and spreading responses on ICAM-1 or fibronectin-coated surfaces. The function of Bam32 in promoting Rac activation and adhesion required tyrosine 139, a known site of phosphorylation by Lyn kinase. After BCR crosslinking by Ag, Bam32-deficient B cells are able to carry out the initial steps of Ag endocytosis and processing, but show diminished ability to form Ag-specific conjugates with T cells and polarize F-actin at the B-T interface. As a result, Bam32-deficient B cells were unable to efficiently activate Ag-specific T cells. Together, these results indicate that Bam32 serves to integrate PI3K and Src kinase signaling to promote Rac-dependent B cell adhesive interactions important for Ag presentation function.