The generation of robust T-cell-dependent humoral immune responses requires the formation and expansion of germinal center structures within the follicular regions of the secondary lymphoid tissues. B-cell proliferation in the germinal center drives ongoing antigen-dependent selection and the generation of highaffinity class-switched plasma and memory B cells. However, the mechanisms regulating B-cell proliferation within this microenvironment are largely unknown. Here, we report that cyclin D3 is uniquely required for germinal center progression. Ccnd3 ؊/؊ mice exhibit a B-cell-intrinsic defect in germinal center maturation and fail to generate an affinity-matured IgG response. We determined that the defect resulted from failed proliferative expansion of GL7 ؉ IgD ؊ PNA ؉ B cells. Mechanistically, sustained expression of cyclin D3 was found to be regulated at the level of protein stability and controlled by glycogen synthase kinase 3 in a cyclic AMP-protein kinase A-dependent manner. The specific defect in proliferative expansion of GL7 ؉ IgD ؊ PNA ؉ B cells in Ccnd3 ؊/؊ mice defines an underappreciated step in germinal center progression and solidifies a role for cyclin D3 in the immune response, and as a potential therapeutic target for germinal center-derived B-cell malignancies.The T-cell-dependent (TD) adaptive immune response is typified by the generation of high-affinity antigen (Ag)-specific memory B cells and antibody-secreting plasma cells (PCs) that have undergone class switch recombination (CSR) to IgG or IgE isotypes. The generation of these cells has long been known to occur in secondary lymphoid tissues within the unique microenvironment of the germinal center (GC). After Ag binding and activation via the B-cell receptor complex (BCR), B cells migrate to the T-cell zone, where additional costimulation is provided by cognate helper T cells. A cohort of these activated B cells go on to colonize GCs, which upon maturation represent an oligoclonal expansion of Ag-specific B cells (14,18).Within the GC, B cells undergo rapid proliferative expansion in response to Ag bound by follicular dendritic cells (FDCs). In humans, histological examination of the GC reveals distinct dark and light zones defined by the presence of proliferating centroblasts and largely nonproliferating centrocytes, respectively. Evidence suggests that centroblasts represent early GC cells that undergo somatic hypermutation (SHM), CSR and proliferative expansion, while centrocytes undergo affinity-based selection and differentiation events, leading to commitment to the memory or PC sublineages and exit from the GC. Although the organization of the GC is less distinct in mice, recent work has shown that chemokine-directed migration, FDC interaction, and proliferation may distinguish early and late GC B cells (1). Despite significant advances in understanding GC B-cell differentiation using multiparameter flow cytometry and intravital imaging, the initial colonization of GC "founder" B cells and their subsequent proliferative expansi...
Twelve strains of psychrophilic bacteria were isolated from cyanobacterial mat samples collected from various water bodies in the McMurdo Dry Valley region of Antarctica. All the isolates were Gram-negative, non-motile, coccoid, psychrophilic, halotolerant bacteria and had C16 : 1 ω7c, C17 : 1 ω8c and C18 : 1 ω9c as the major fatty acids, ubiquinone-8 as the respiratory quinone and DNA G+C content of 41–46 mol%. Based on these characteristics, the isolates were assigned to the genus Psychrobacter. Based on their SDS-PAGE profiles, the 12 isolates could be categorized into three groups. Six isolates of Group I were identified as representing strains of Psychrobacter okhotskensis. However, using detailed phenotypic and chemotaxonomic characteristics and phylogenetic analysis based on their 16S rRNA gene sequences, strain CMS 39T, the only strain from Group II, and strain CMS 56T, a representative strain of Group III, were different from each other and from all recognized species of Psychrobacter. Therefore, it is proposed to classify CMS 39T (=DSM 15337T=MTCC 4208T) and CMS 56T (=DSM 15339T=MTCC 4386T) as representing the type strains of novel species of Psychrobacter, for which the names Psychrobacter vallis sp. nov. and Psychrobacter aquaticus sp. nov., respectively, are proposed.
Acyl-lipid desaturases are enzymes that convert a C-C single bond into a C=C double bond in fatty acids that are esterified to membrane-bound glycerolipids. Four types of acyl-lipid desaturase, namely DesA, DesB, DesC, and DesD, acting at the Delta12, Delta15, Delta9, and Delta6 positions of fatty acids respectively, have been characterized in cyanobacteria. These enzymes are specific for fatty acids bound to the sn-1 position of glycerolipids. In the present study, we have cloned two putative genes for a Delta9 desaturase, designated desC1 and desC2, from Nostoc species. The desC1 gene is highly similar to the desC gene that encodes a Delta9 desaturase that acts on C18 fatty acids at the sn-1 position. Homologues of desC2 are found in genomes of cyanobacterial species in which Delta9-desaturated fatty acids are esterified to the sn-2 position. Heterologous expression of the desC2 gene in Synechocystis sp. PCC 6803, in which a saturated fatty acid is found at the sn-2 position, revealed that DesC2 could desaturate this fatty acid at the sn-2 position. These results suggest that the desC2 gene is a novel gene for a Delta9 acyl-lipid desaturase that acts on fatty acids esterified to the sn-2 position of glycerolipids.
The marginal zone is a cellular niche bordering the marginal sinus of the spleen that contains specialized B-cell and macrophage subsets poised to capture bloodborne antigens. Marginal zone B cells are retained in this niche by integrin-mediated signaling induced by G protein-coupled receptors (GPCRs) and, likely, the B-cell receptor (BCR). Sphingosine-1-phosphate (S1P) signaling via the S1P family of GPCRs is known to be essential for B-cell localization in the marginal zone, but little is known about the downstream signaling events involved. Here, we demonstrate that the adaptor protein SHEP1 is required for marginal zone B-cell maturation. SHEP1 functions in concert with the scaffolding protein CasL, because we show that SHEP1 and CasL are constitutively associated in B cells. SHEP1 association is required for the BCR or S1P receptor(s) to induce the conversion of CasL into its serine/threonine hyperphosphorylated form, which is important for lymphocyte adhesion and motility. Thus, SHEP1 orchestrates marginal zone B-cell movement and retention as a key downstream effector of the BCR and S1P receptors.Cas-Hef1-associated signal transducer | Sh2d3c | migration | sphingosine-1-phosphate | signaling A dhesion and migration are required for B-cell development, differentiation, and function. B cells traffic to follicular regions in the secondary lymphoid tissues in response to chemokines produced by the follicular stroma (1). In the spleen, the marginal zone (MZ) surrounding the white pulp contains a subset of B cells that are poised to respond to antigens delivered via the blood sinuses. MZ B cells are retained in this niche by integrin signaling induced by "outside-in" signaling via G protein-coupled receptors (GPCRs) and, likely, the B-cell receptor (BCR) (2).The lipid mediator, sphingosine-1-phosphate (S1P), has been shown to be a prominent factor in guiding B cells to the MZ niche (3, 4). Similar to chemokine receptors, such as CXCR4 and CXCR5, S1P receptors act in B cells by coupling to heterotrimeric G proteins and mobilizing calcium (5). S1P has also been shown to induce proximal phosphorylation of focal adhesion kinase and paxillin in fibroblasts, and promote the phosphorylation of downstream adaptors and activation of Ras family GTPases to affect adhesion and migration (6). MZ B cells are particularly sensitive to deletions of certain GTPases, GAPs (GTPase-activating proteins), and GEFs that promote integrin activation, cell adhesion, and cell migration. For example, deficiencies in Rap1A, Rap1B, DOCK2, or the RhoGEF Lsc result in the loss of B-cell chemotactic responses and in a marked reduction in MZ B cells (7-11). These findings are consistent with the requisite roles of LFA-1 and VLA-4 integrins, which are highly expressed on MZ B cells compared with follicular B cells (12, 13). BCR and CXCR4 signaling have also been shown to induce the tyrosine phosphorylation of the scaffolding protein CasL/HEF1 (14, 15). Tyrosine phosphorylation of CasL is required for its interaction with the adaptor CrkL, allowi...
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