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1.
Carey JB Moffatt-Blue CS Watson LC Gavin AL Feeney AJ 《The Journal of experimental medicine》2008,205(9):2043-2052
Marginal zone (MZ) B cells resemble fetally derived B1 B cells in their innate-like rapid responses to bacterial pathogens, but the basis for this is unknown. We report that the MZ is enriched in “fetal-type” B cell receptors lacking N regions (N−). Mixed bone marrow (BM) chimeras, made with adult terminal deoxynucleotidyl transferase (TdT)+/+ and TdT−/− donor cells, demonstrate preferential repertoire-based selection of N− B cells into the MZ. Reconstitution of irradiated mice with adult TdT+/+ BM reveals that the MZ can replenish N− B cells in adult life via repertoire-based selection and suggest the possibility of a TdT-deficient precursor population in the adult BM. The mixed chimera data also suggest repertoire-based bifurcations into distinct BM and splenic maturation pathways, with mature “recirculating” BM B cells showing a very strong preference for N+ complementarity-determining region (CDR) 3 compared with follicular B cells. Because the T1 and MZ compartments are both the most enriched for N− H-CDR3, we propose a novel direct T1→MZ pathway and identify a potential T1–MZ precursor intermediate. We demonstrate progressive but discontinuous repertoire-based selection throughout B cell development supporting multiple branchpoints and pathways in B cell development. Multiple differentiation routes leading to MZ development may contribute to the reported functional heterogeneity of the MZ compartment. 相似文献
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Jeffrey C. Rathmell Sylvie Fournier Bennett C. Weintraub James P. Allison Christopher C. Goodnow 《The Journal of experimental medicine》1998,188(4):651-659
Peripheral tolerance mechanisms normally prevent delivery of T cell help to anergic self-reactive B cells that accumulate in the T zones of spleen and lymph nodes. Chronic exposure to self-antigens desensitizes B cell antigen receptor (BCR) signaling on anergic B cells so that they are not stimulated into clonal expansion by CD4+ T cells but instead are eliminated by Fas (CD95)-induced apoptosis. Because a range of BCR-induced signals and responses are repressed in anergic B cells, it is not known which of these are critical to regulate for Fas-mediated peripheral tolerance. Display of the costimulatory molecule, B7.2 (CD86), represents a potentially important early response to acute BCR engagement that is poorly induced by antigen on anergic B cells. We show here that restoring B7.2 expression on tolerant B cells using a constitutively expressed B7.2 transgene is sufficient to prevent Fas-mediated deletion and to trigger extensive T cell–dependent clonal expansion and autoantibody secretion in the presence of specific T cells. Dysregulated expression of B7.2 on tolerant B cells caused a more extreme reversal of peripheral tolerance than that caused by defects in Fas or Fas ligand, and resulted in T cell–dependent clonal expansion and antibody secretion comparable in magnitude to that made by foreign antigen-specific B cells. These findings demonstrate that repression of B7.2 is critical to eliminate autoreactive B cells by Fas in B cell–T cell interactions. The possible role of B7.2 dysregulation in systemic autoimmune diseases is discussed. 相似文献
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Michelle S.J. Lee Takeshi Inoue Wataru Ise Julia Matsuo-Dapaah James B. Wing Burcu Temizoz Kouji Kobiyama Tomoya Hayashi Ashwini Patil Shimon Sakaguchi A. Katharina Simon Jelena S. Bezbradica Satoru Nagatoishi Kouhei Tsumoto Jun-Ichiro Inoue Shizuo Akira Tomohiro Kurosaki Ken J. Ishii Cevayir Coban 《The Journal of experimental medicine》2022,219(2)
The germinal center (GC) is a site where somatic hypermutation and clonal selection are coupled for antibody affinity maturation against infections. However, how GCs are formed and regulated is incompletely understood. Here, we identified an unexpected role of Tank-binding kinase-1 (TBK1) as a crucial B cell–intrinsic factor for GC formation. Using immunization and malaria infection models, we show that TBK1-deficient B cells failed to form GC despite normal Tfh cell differentiation, although some malaria-infected B cell–specific TBK1-deficient mice could survive by GC-independent mechanisms. Mechanistically, TBK1 phosphorylation elevates in B cells during GC differentiation and regulates the balance of IRF4/BCL6 expression by limiting CD40 and BCR activation through noncanonical NF-κB and AKTT308 signaling. In the absence of TBK1, CD40 and BCR signaling synergistically enhanced IRF4 expression in Pre-GC, leading to BCL6 suppression, and therefore failed to form GCs. As a result, memory B cells generated from TBK1-deficient B cells fail to confer sterile immunity upon reinfection, suggesting that TBK1 determines B cell fate to promote long-lasting humoral immunity. 相似文献
6.
Ming-Chao Zhong Yan Lu Jin Qian Yingzi Zhu Lingli Dong Astrid Zahn Javier M. Di Noia Danielle Karo-Atar Irah L. King Andr Veillette 《The Journal of experimental medicine》2021,218(3)
Expression of the signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) is critical for the germinal center (GC) reaction and T cell–dependent antibody production. However, when SAP is expressed normally, the role of the associated SLAM family receptors (SFRs) in these processes is nebulous. Herein, we established that in the presence of SAP, SFRs suppressed the expansion of the GC reaction but facilitated the generation of antigen-specific B cells and antibodies. SFRs favored the generation of antigen-reactive B cells and antibodies by boosting expression of pro-survival effectors, such as the B cell antigen receptor (BCR) and Bcl-2, in activated GC B cells. The effects of SFRs on the GC reaction and T cell–dependent antibody production necessitated expression of multiple SFRs, both in T cells and in B cells. Hence, while in the presence of SAP, SFRs inhibit the GC reaction, they are critical for the induction of T cell–mediated humoral immunity by enhancing expression of pro-survival effectors in GC B cells. 相似文献
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HTLV-1 propels untransformed CD4 lymphocytes into the cell cycle while protecting CD8 cells from death
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Sibon D Gabet AS Zandecki M Pinatel C Thête J Delfau-Larue MH Rabaaoui S Gessain A Gout O Jacobson S Mortreux F Wattel E 《The Journal of clinical investigation》2006,116(4):974-983
Human T cell leukemia virus type 1 (HTLV-1) infects both CD4+ and CD8+ lymphocytes, yet it induces adult T cell leukemia/lymphoma (ATLL) that is regularly of the CD4+ phenotype. Here we show that in vivo infected CD4+ and CD8+ T cells displayed similar patterns of clonal expansion in carriers without malignancy. Cloned infected cells from individuals without malignancy had a dramatic increase in spontaneous proliferation, which predominated in CD8+ lymphocytes and depended on the amount of tax mRNA. In fact, the clonal expansion of HTLV-1–positive CD8+ and CD4+ lymphocytes relied on 2 distinct mechanisms — infection prevented cell death in the former while recruiting the latter into the cell cycle. Cell cycling, but not apoptosis, depended on the level of viral-encoded tax expression. Infected tax-expressing CD4+ lymphocytes accumulated cellular defects characteristic of genetic instability. Therefore, HTLV-1 infection establishes a preleukemic phenotype that is restricted to CD4+ infected clones. 相似文献
9.
Rebecca A. Porritt Lisa Paschold Magali Noval Rivas Mary Hongying Cheng Lael M. Yonker Harsha Chandnani Merrick Lopez Donjete Simnica Christoph Schultheiß Chintda Santiskulvong Jennifer Van Eyk John K. McCormick Alessio Fasano Ivet Bahar Mascha Binder Moshe Arditi 《The Journal of clinical investigation》2021,131(10)
Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vβ chains results in Vβ skewing, whereby T cells with specific Vβ chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCRβ variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the Vβ chain encoded by TRBV11-2 (Vβ21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C. 相似文献
10.
Christina E. Barkauskas Michael J. Cronce Craig R. Rackley Emily J. Bowie Douglas R. Keene Barry R. Stripp Scott H. Randell Paul W. Noble Brigid L.M. Hogan 《The Journal of clinical investigation》2013,123(7):3025-3036
Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C–positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing “alveolospheres,” which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα+ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung. 相似文献
11.
Radhika Goenka Andrew H. Matthews Bochao Zhang Patrick J. O’Neill Jean L. Scholz Thi-Sau Migone Warren J. Leonard William Stohl Uri Hershberg Michael P. Cancro 《The Journal of experimental medicine》2014,211(1):45-56
We have assessed the role of B lymphocyte stimulator (BLyS) and its receptors in the germinal center (GC) reaction and affinity maturation. Despite ample BLyS retention on B cells in follicular (FO) regions, the GC microenvironment lacks substantial BLyS. This reflects IL-21–mediated down-regulation of the BLyS receptor TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) on GC B cells, thus limiting their capacity for BLyS binding and retention. Within the GC, FO helper T cells (TFH cells) provide a local source of BLyS. Whereas T cell–derived BLyS is dispensable for normal GC cellularity and somatic hypermutation, it is required for the efficient selection of high affinity GC B cell clones. These findings suggest that during affinity maturation, high affinity clones rely on TFH-derived BLyS for their persistence.The affinity maturation of antibodies involves competition among B cells expressing novel specificities generated by somatic hypermutation (SHM). This process occurs in germinal centers (GCs), transient structures formed during T cell–dependent immune responses that enable the preferential survival of B cells producing higher affinity antibodies. Ultimately, this competitive selection process preserves GC B cells with improved antigen affinity and eliminates those that lose specificity or gain autoreactivity. The mechanisms responsible for differential survival remain uncertain but involve tripartite interactions between the GC B cells, FO DCs (FDCs), and T FO helper (TFH) cells. How the B cell receptor (BCR) drives this affinity-dependent selection process is debated. Although loss of BCR-associated signals disrupt GC kinetics (Wang and Carter, 2005; Huntington et al., 2006), recent findings suggest that antigen capture may be its primary function because BCR signaling is damped in most GC B cells by negative regulatory mechanisms (Khalil et al., 2012). This is consistent with models whereby GC B cells compete for antigen displayed on FDCs to mediate effective MHCII-restricted antigen presentation, thereby fostering sustained TFH interactions, which in turn promote GC B cell survival (Allen and Cyster, 2008; McHeyzer-Williams et al., 2009; Victora and Nussenzweig, 2012). This idea is further supported by observations indicating that cognate TFH interactions are a limiting factor in affinity maturation (Schwickert et al., 2011). Thus, higher affinity GC B cells can capture and present antigen more effectively, enabling their preferential access to TFH cells and facilitating positive selection (Victora et al., 2010; Schwickert et al., 2011).Despite mounting evidence for this model, the mechanism whereby TFH interactions mediate selective survival of higher affinity GC B cells remains unclear. T–B interactions via receptors such as co-stimulatory molecules, death receptor ligands, and soluble survival factors are probably involved. However, the precise identities and relative roles of these molecules remain obscure because most potential candidates also play roles in GC initiation or maintenance on their own. Therefore, separating these functions from direct roles in the preferential selection of high affinity clones has proven difficult. For example, the initiation and maintenance of GCs rely on sustained CD40/CD40L signals, and death receptors such as Fas/FasL interactions act to limit GC responses (Foy et al., 1993; Han et al., 1995; Hao et al., 2008). Similarly, soluble mediators such as IL-21 are essential for maintenance of GC B cell character as well as fate choices (Linterman et al., 2010; Zotos et al., 2010).The B lineage survival cytokine, B lymphocyte stimulator (BLyS, also termed B cell activating factor [BAFF]), plays a key role in setting thresholds for BCR-mediated selection among naive B cells (Cancro, 2004), making it an attractive candidate for mediating analogous processes in the GC. Consistent with this notion, GC responses prematurely terminate in mice with either global BLyS deficiency or defects in BLyS receptor 3 (BR3, also known as BAFFR) signaling (Rahman et al., 2003). Straightforward interpretation of these findings is difficult, because both BLyS-deficient and BR3 mutant mice are severely B lymphopenic (Moore et al., 1999; Schneider et al., 1999; Yan et al., 2001a). Thus, deficits in naive B cell numbers might explain an inability to sustain GC reactions because GCs are resupplied from the naive pools (Schwickert et al., 2007). Moreover, defects in FDC network maturation and TFH function also occur in B lymphopenic environments (Rahman et al., 2003; Johnston et al., 2009). Thus, whether BLyS plays a direct role in GC B cell selection and affinity maturation has remained unclear.To better understand how BLyS influences GC function, we investigated the distribution and expression of BLyS and its receptors during GC responses in normal mice. We find that BLyS is spatially segregated between the follicles and GCs, as well as within the GCs, where it is found mainly in the light zone (LZ). Thus, in contrast to FO B cells, GC B cells lack appreciable surface-bound BLyS. This results from profound down-regulation of the BLyS receptor, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which occurs as FO B cells adopt GC B character after IL-21 signals in the context of BCR cross-linking and CD40 co-stimulation. However, in the LZ BLyS is highly expressed by and associated with FO T cells, both helper (TFH) and regulatory (TFR). Mixed BM chimeras that lack T cell–derived BLyS have normal GC cellularity and low-affinity IgM and IgG1 antibodies but exhibit significant reductions in high affinity antibody. Moreover, although SHM occurs under these conditions, the patterns of mutation are broadly distributed and show a lower strength of positive selection. Together, these findings indicate that TFH-derived BLyS is required to preserve high affinity clones among antigen binding GC B cells. 相似文献
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为了解AML-M2a细胞体外诱导TCRVβ亚家族T细胞的表达和克隆性增殖情况,利用混合淋巴细胞/肿瘤细胞培养(MLTC)体外获取AML-M2a细胞诱导的T细胞,并以RT-PCR扩增4例M2a患外周血单个核细胞和4例AML-M 2a细胞诱导的T细胞中的24个TCRVβ亚家族基因的互补决定区3(CDR3),阳性产物进一步经基因扫描分析从而确定AML-M2a细胞体内外诱导的TCRVβ亚家族T细胞的克隆性增殖情况,结果显示:4例AML-M2a细胞体内外诱导的Vβ亚家族T细胞表达情况相似,其中3例AML-M2a细胞体内外诱导的一个或两个Vβ亚家族T细胞呈克隆性增殖特点,结论:AML-M2a细胞体内外选择性诱导不同的TCRVβ亚家族T细胞克隆性增殖可能是患T细胞对AML-M2a细胞相关抗原刺激所产生的一种特异性细胞免疫反应,体内外环境的不同对Vβ亚家族T细胞的克隆性增殖情况有一定的影响。 相似文献
13.
GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes 总被引:9,自引:0,他引:9
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Insulin-dependent type 1 diabetes is an autoimmune disease mediated by T lymphocytes recognizing pancreatic islet cell antigens. Glutamic acid decarboxylase 65 (GAD65) appears to be an important autoantigen in the disease. However, T cells from both patients with type 1 diabetes and healthy subjects vigorously proliferate in response to GAD65 stimulation ex vivo, leading us to postulate that the critical event in the onset of human diabetes is the activation of autoreactive T cells. Thus, we investigated whether GAD65-reactive T cells in patients with diabetes functioned as previously activated memory T cells, no longer requiring a second, costimulatory signal for clonal expansion. We found that in patients with new-onset type 1 diabetes, GAD65-reactive T cells were strikingly less dependent on CD28 and B7-1 costimulation to enter into cell cycle and proliferate than were equivalent cells derived from healthy controls. We hypothesize that these autoreactive T cells have been activated in vivo and have differentiated into memory cells, suggesting a pathogenic role in type 1 diabetes. In addition, we observed different effects with selective blockade of either B7-1 or B7-2 molecules; B7-1 appears to deliver a negative signal by engaging CTLA-4, while B7-2 engagement of CD28 upregulates T cell proliferation and cytokine secretion. 相似文献
14.
In situ studies of the primary immune response to (4-hydroxy-3- nitrophenyl)acetyl. IV. Affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self- tolerance 总被引:11,自引:7,他引:4
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《The Journal of experimental medicine》1995,182(6):1635-1644
Germinal centers (GCs) are the sites of antigen-driven V(D)J gene hypermutation and selection necessary for the generation of high affinity memory B lymphocytes. Despite the antigen dependence of this reaction, injection of soluble antigen during an established primary immune response induces massive apoptotic death in GC B cells, but not in clonally related populations of nonfollicular B lymphoblasts and plasmacytes. Cell death in GCs occurs predominantly among light zone centrocytes, is antigen specific, and peaks within 4-8 h after injection. Antigen-induced programmed death does not involve cellular interactions mediated by CD40 ligand (CD40L) or Fas; disruption of GCs by antibody specific for CD40L was not driven by apoptosis and C57BL/6.lpr mice, though unable to express the Fas death trigger, remained fully susceptible to soluble antigen. Single injections of antigen did not significantly decrease GC numbers or average size, but repeated injections during an 18-h period resulted in fewer and substantially smaller GCs. As cell loss appeared most extensive in the light zone, decreased GC cellularity after prolonged exposure to soluble antigen implies that the Ig- centroblasts of the dark zone may require replenishment from light zone cells that have survived antigenic selection. GC cell death is avidity-dependent; oligovalent antigen induced relatively little apoptosis and GC B cells that survived long exposures to multivalent antigen expressed atypical VDJ rearrangements unlikely to encode high affinity antibody. Antigen- induced apoptotic death in GCs may represent a mechanism for the peripheral deletion of autoreactive B cell mutants much as the combinatorial repertoire of immature B lymphocytes is censored in the bone marrow. 相似文献
15.
Glucocorticoid-mediated control of the activation and clonal deletion of peripheral T cells in vivo 总被引:5,自引:4,他引:5
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《The Journal of experimental medicine》1993,177(5):1239-1246
Poly- and oligoclonal T cell stimuli like anti-CD3 epsilon monoclonal antibody or Staphylococcus aureus enterotoxin B (SEB), injected at doses that per se are not lethal, provoke acute death within less than 24 h, provided that endogenous glucocorticoids (GC) are depleted by adrenalectomy or by injection of saturating amounts of the GC receptor antagonist RU-38486 (mifepristone). Pharmacological doses of the GC agonist dexamethasone (DEX) alter the in vivo response of splenic V beta 8+ T cells to SEB, thus impeding the expansion of such cells and causing their rapid (3 d) clonal deletion. In contrast, coadministration of RU-38486 counteracts a SEB-induced early (12 h) reduction of V beta 8+CD4+ and V beta 8+CD8+ spleen cells. In vivo T cell stimulation by injection of bacterial superantigen induces a rapid (peak at 90-120 min) increase in corticosterone serum levels, suggesting that endogenous GC might control early T cell activation. Accordingly, kinetic studies revealed that RU-38486 has to be administered within 2 h after superantigen administration to exert its lethal effect. Similarly, exogenous GC must be injected during this critical phase (2 h) to rescue animals from acute death induced by coinjection of SEB and D-galactosamine (GalN). Adrenalectomy, injection of RU-38486 and priming with GalN per se provoke the programmed death of peripheral CD4+ and CD8+ T cells. Thus, three manipulations that sensitize mice for the lethal effect of T cell stimulation also exert a proapoptotic effect on peripheral T cells. In synthesis, endogenous and exogenous GC regulate T cell responses and determine the propensity of peripheral T cells to undergo apoptosis. 相似文献
16.
Masaki Hikida Stefano Casola Noriko Takahashi Tomohiro Kaji Toshitada Takemori Klaus Rajewsky Tomohiro Kurosaki 《The Journal of experimental medicine》2009,206(3):681-689
Resting antigen-experienced memory B cells are thought to be responsible for the more rapid and robust antibody responses after antigen reencounter, which are the hallmark of memory humoral responses. The molecular basis for the development and survival of memory B cells remains largely unknown. We report that phospholipase C (PLC) γ2 is required for efficient formation of germinal center (GC) and memory B cells. Moreover, memory B cell homeostasis is severely hampered by inducible loss of PLC-γ2. Accordingly, mice with a conditional deletion of PLC-γ2 in post-GC B cells had an almost complete abrogation of the secondary antibody response. Collectively, our data suggest that PLC-γ2 conveys a survival signal to GC and memory B cells and that this signal is required for a productive secondary immune response.Humoral memory is characterized by recall immune responses, which are more rapid than the primary response, and by production of higher serum titers of antigen-specific antibodies, mostly of the IgG isotype. The prevailing view is that antigen-specific B cells are maintained as a pool of memory B cells after clonal expansion during the primary immune response (1–4). Most memory B cells have been thought to originate from the germinal center (GC) reaction. In the GC, the combined processes of somatic hypermutation and selection based on the affinity of the B cell receptor (BCR) for the antigen are responsible for the generation of high-affinity antibody variants that ultimately differentiate into long-lived plasma cells or long-lived memory B cells (5, 6). The GC is also a preferential site of antibody class switching. In the GC reaction, de novo–generated antigen-specific memory B cells are thought to acquire intrinsically different traits from their naive predecessors, accounting for faster and heightened secondary responses. Thus, understanding the mechanism by which memory B cells are generated and maintained, as well as the intrinsic functional differences between naive and memory B cells, is of fundamental interest to reveal the basis of immunological memory.The analysis of gene-targeted mice lacking the cytoplasmic tail of the IgG1 or IgE BCR has revealed its essential function in secondary responses (7, 8). In response to T cell–dependent antigens, mice harboring the tailless IgG1 had ∼25-fold fewer IgG1-expressing B cells, presumably reflecting a reduced number of GC and memory B cells and raising the possibility that the IgG1 cytoplasmic tail is involved in the generation and/or maintenance of memory B cells or their direct precursors. Two non–mutually exclusive models have been proposed to explain the function of the IgG1 tail (9). First, it may be required for efficient BCR-mediated internalization and, hence, presentation of antigen to T cells (10). As T cells facilitate productive IgG1 memory responses, inefficient antigen presentation by mutant B cells could lead to defective proliferation of GC B cells and, consequently, diminished generation of memory B cells. Second, the IgG1 tail may contribute to memory responses by modifying the BCR signal, for example by transmitting survival signals to memory B cells and/or their direct precursors (11, 12).To define the signaling molecules required for the establishment and maintenance of memory B cells, we focused on the function of phospholipase C (PLC) γ2 because this enzyme is well recognized as an important component of the BCR signaling pathway (13, 14). Indeed, PLC-γ2–deficient mice show a differentiation block between the immature and mature B cell stages owing to defective BCR signaling (15, 16). However, given the expression of PLC-γ2 in several immune cell types (17, 18) and the premature block in B cell development in conventional PLC-γ2 KO mice, these mice are not ideal for analyzing the role of PLC-γ2 in a B cell–intrinsic manner during T cell–dependent antibody responses. Thus, we used conditional mice in which PLC-γ2 function was specifically inactivated in GC B cells and in an inducible manner. We show in this paper that PLC-γ2 is required for the efficient generation and maintenance of memory B cells, probably through the delivery of a prosurvival signal. 相似文献
17.
Miletic AV Anzelon-Mills AN Mills DM Omori SA Pedersen IM Shin DM Ravetch JV Bolland S Morse HC Rickert RC 《The Journal of experimental medicine》2010,207(11):2407-2420
The inositol phosphatases phosphatase and tensin homologue (PTEN) and Src homology 2 domain-containing inositol phosphatase (SHIP) negatively regulate phosphatidylinositol-3-kinase (PI3K)-mediated growth, survival, and proliferation of hematopoietic cells. Although deletion of PTEN in mouse T cells results in lethal T cell lymphomas, we find that animals lacking PTEN or SHIP in B cells show no evidence of malignancy. However, concomitant deletion of PTEN and SHIP (bPTEN/SHIP(-/-)) results in spontaneous and lethal mature B cell neoplasms consistent with marginal zone lymphoma or, less frequently, follicular or centroblastic lymphoma. bPTEN/SHIP(-/-) B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27(kip1) and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP(-/-) B cells proliferate to the prosurvival factor B cell activating factor (BAFF). Interestingly, although BAFF availability may promote lymphoma progression, we demonstrate that BAFF is not required for the expansion of transferred bPTEN/SHIP(-/-) B cells. This study reveals that PTEN and SHIP act cooperatively to suppress B cell lymphoma and provides the first direct evidence that SHIP is a tumor suppressor. As such, assessment of both PTEN and SHIP function are relevant to understanding the etiology of human B cell malignancies that exhibit augmented activation of the PI3K pathway. 相似文献
18.
Raud Razzaghi Shreya Agarwal Nikita Kotlov Olga Plotnikova Krystle Nomie Da Wei Huang George W. Wright Grace A. Smith Moyi Li Katsuyoshi Takata Maryam Yamadi Chen Yao John J. OShea James D. Phelan Stefania Pittaluga David W. Scott Jagan R. Muppidi 《The Journal of experimental medicine》2021,218(3)
Fas is highly expressed on germinal center (GC) B cells, and mutations of FAS have been reported in diffuse large B cell lymphoma (DLBCL). Although GC-derived DLBCL has better overall outcomes than other DLBCL types, some cases are refractory, and the molecular basis for this is often unknown. We show that Fas is a strong cell-intrinsic regulator of GC B cells that promotes cell death in the light zone, likely via T follicular helper (Tfh) cell–derived Fas ligand. In the absence of Fas, GCs were more clonally diverse due to an accumulation of cells that did not demonstrably bind antigen. FAS alterations occurred most commonly in GC-derived DLBCL, were associated with inferior outcomes and an enrichment of Tfh cells, and co-occurred with deficiency in HVEM and PD-L1 that regulate the Tfh–B cell interaction. This work shows that Fas is critically required for GC homeostasis and suggests that loss of Tfh-mediated counterselection in the GC contributes to lethality in GC-derived lymphoma. 相似文献
19.
Human dendritic cells. Enrichment and characterization from peripheral blood 总被引:60,自引:11,他引:49
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W C Van Voorhis L S Hair R M Steinman G Kaplan 《The Journal of experimental medicine》1982,155(4):1172-1187
Previous studies demonstrated that lymphoid tissues of mice and rats contain small numbers (less than 1 percent of nucleated cells) of dendritic cells (DC) with special cytologic, surface, and functional properties. We show here that similar DC represent 0.1-0.5 percent of human peripheral blood mononuclear cells. DC can be enriched to 20-60 percent purity by a multistep procedure analogous to that used in mice. Adherent peripheral blood mononuclear cells are cultured overnight, and the released cells are depleted of monocytes and B cells by readherence to plastic, rosetting with erythrocytes coated with anti-human IgG, and centrifugation in dense albumin columns. Enriched DC have similar cytologic features to rodent DC by light and electron microscopy. DC express HLA, and HLA-DR and the leukocyte-common antigens. They lack phagocytic capacity, receptors for antibody-coated and neuraminidase-treated erythrocytes, surface and intracellular Ig, esterase, peroxidase, and azurophilic granules. DC do not react with several monoclonal antibodies directed to phagocytes (OKM 1, “mac-1,” 63D3, and 61D3) and T cells (OKT 3, 6, 8). Unlike the mouse, human DC express complement receptors. When maintained in culture for 4 d, human DC did not give rise to either B cells or monocytes. Therefore, DC identified by cytologic criteria are distinct from other leukocytes. Enriched populations of DC have been compared to fractions enriched in monocytes, B cells, and T cells in three functional assays: stimulation of the primary allogeneic mixed leukocyte reaction, stimulation of the primary syngeneic MLR, and accessory function for the proliferation of periodate- modified T cells. In each case, the DC fraction was 10-fold or more active than other cell fractions. We conclude that DC circulate in man, and represent the principal cell type required for the initiation of several immune responses. 相似文献
20.
Francesco R. Simonetti Hao Zhang Garshasb P. Soroosh Jiayi Duan Kyle Rhodehouse Alison L. Hill Subul A. Beg Kevin McCormick Hayley E. Raymond Christopher L. Nobles John K. Everett Kyungyoon J. Kwon Jennifer A. White Jun Lai Joseph B. Margolick Rebecca Hoh Steven G. Deeks Frederic D. Bushman Janet D. Siliciano Robert F. Siliciano 《The Journal of clinical investigation》2021,131(3)
Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4+ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone’s response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts. 相似文献