IL-15 regulates immature B-cell homing in an Ly49D-, IL-12–, and IL-18–dependent manner

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 50-59 ◽  
Author(s):  
Gili Hart ◽  
Tamar Avin-Wittenberg ◽  
Idit Shachar
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Dependent Manner ◽  
Cell Repertoire ◽  
Cell Homing ◽  
Final Maturation ◽  
Immature B Cells ◽  
Ifn Γ

To complete their maturation and participate in the humoral immune response, immature B cells that leave the bone marrow are targeted to specific areas in the spleen, where they differentiate into mature cells. Previously, we showed that immature B cells actively down-regulate their integrin-mediated migration to lymph nodes or to sites of inflammation, enabling their targeting to the spleen for final maturation. This inhibition is mediated by IFN-γ, which is transcribed and secreted at low levels by these immature B cells; IFN-γ expression is extinguished following B-cell maturation. Stimulation of the MHC class I receptor, Ly49D, triggers a signaling cascade that increases transcription of both IL-12 (p40) and IL-18; these, in turn, induce the secretion of IFN-γ. In the present study, we demonstrate that Ly49D-dependent secretion of IL-12 and IL-18 induces IL-15 expression by immature B cells, and that these 3 factors together regulate IFN-γ production that inhibits their ability to home to the lymph nodes or to sites of inflammation. Thus, IL-15 controls immature B-cell homing, resulting in shaping the B-cell repertoire to enable an efficient immune response.

scholarly journals Phospholipid flippases enable precursor B cells to flee engulfment by macrophages

2018 ◽  
Vol 115 (48) ◽  
pp. 12212-12217 ◽  
Author(s):  
Katsumori Segawa ◽  
Yuichi Yanagihashi ◽  
Kyoko Yamada ◽  
Chigure Suzuki ◽  
Yasuo Uchiyama ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
B Cells ◽  
B Cell ◽  
Developmental Stages ◽  
Peritoneal Macrophages ◽  
Dependent Manner ◽  
Wild Type ◽  
Immature B Cells ◽  
T Lymphoma ◽  
Precursor B Cells

ATP11A and ATP11C, members of the P4-ATPases, are flippases that translocate phosphatidylserine (PtdSer) from the outer to inner leaflet of the plasma membrane. Using the W3 T lymphoma cell line, we found that Ca2+ ionophore-induced phospholipid scrambling caused prolonged PtdSer exposure in cells lacking both the ATP11A and ATP11C genes. ATP11C-null (ATP11C−/y) mutant mice exhibit severe B-cell deficiency. In wild-type mice, ATP11C was expressed at all B-cell developmental stages, while ATP11A was not expressed after pro−B-cell stages, indicating that ATP11C−/y early B-cell progenitors lacked plasma membrane flippases. The receptor kinases MerTK and Axl are known to be essential for the PtdSer-mediated engulfment of apoptotic cells by macrophages. MerTK−/− and Axl−/− double deficiency fully rescued the lymphopenia in the ATP11C−/y bone marrow. Many of the rescued ATP11C−/y pre-B and immature B cells exposed PtdSer, and these cells were engulfed alive by wild-type peritoneal macrophages, in a PtdSer-dependent manner. These results indicate that ATP11A and ATP11C in precursor B cells are essential for rapidly internalizing PtdSer from the cell surface to prevent the cells’ engulfment by macrophages.

Bim establishes the B-cell repertoire from early to late in the immune response

2020 ◽  
Author(s):  
Akiko Sugimoto-Ishige ◽  
Michishige Harada ◽  
Miho Tanaka ◽  
Tommy Terooatea ◽  
Yu Adachi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Late Response ◽  
Cell Repertoire ◽  
High Affinity ◽  
B Cell Repertoire

Abstract In T cell-dependent antibody responses, some of the activated B cells differentiate along extrafollicular pathways into low-affinity memory and plasma cells, whereas others are involved in subsequent germinal center (GC) formation in follicular pathways, in which somatic hypermutation and affinity maturation occur. The present study demonstrated that Bim, a proapoptotic BH3-only member of the Bcl-2 family, contributes to the establishment of the B-cell repertoire from early to late stages of immune responses to T cell-dependent antigens. Extrafollicular plasma cells grew in the spleen during the early immune response, but their numbers rapidly declined with the appearance of GC-derived progeny in wild-type mice. By contrast, conditional Bim deficiency in B cells resulted in expansion of extrafollicular IgG1+ antibody-forming cells (AFCs) and this expansion was sustained during the late response, which hampered the formation of GC-derived high-affinity plasma cells in the spleen. Approximately 10% of AFCs in mutant mice contained mutated VH genes; thus, Bim deficiency appears not to impede the selection of high-affinity AFC precursor cells. These results suggest that Bim contributes to the replacement of low-affinity antibody by high-affinity antibody as the immune response progresses.

scholarly journals Mad3 Negatively Regulates B Cell Differentiation in the Spleen by Inducing Id2 Expression

2010 ◽  
Vol 21 (11) ◽  
pp. 1864-1871 ◽  
Author(s):  
Yael Gore ◽  
Frida Lantner ◽  
Gili Hart ◽  
Idit Shachar
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Negative Regulator ◽  
Maturation Process ◽  
B Cell Differentiation ◽  
Final Maturation ◽  
Immature B Cells

Immature B cells migrate to the spleen where they differentiate into mature cells. This final maturation step is crucial to enable B cells to become responsive to antigens and to participate in the immune response. Previously, we showed that Id2 acts as a negative regulator of the differentiation of immature B cells occurring in the spleen. Id2 expression has been found to depend on Myc–Max–Mad transcriptional complexes in mammary epithelial cells. Nearly all studies to date have shown that Mad proteins inhibit proliferation, presumably by antagonizing the function of Myc proteins. In the current study, we followed the Mad family members during peripheral B cell differentiation. We show that Mad3 actively regulates B cell differentiation. Our results demonstrate that high expression levels of Mad3 in immature B cells induce Id2 expression, which inhibits transcription of genes essential for B cell differentiation. During their differentiation to mature cells, B cells reduce their Mad3 expression, enabling the maturation process to occur.

scholarly journals Role of IgD in the immune response and tolerance. I. Anti-delta pretreatment facilitates tolerance induction in adult B cells in vitro.

1977 ◽  
Vol 146 (6) ◽  
pp. 1473-1483 ◽  
Author(s):  
D W Scott ◽  
J E Layton ◽  
G J Nossal
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Tolerance Induction ◽  
Spleen Cells ◽  
Cell Compartment ◽  
Immature B Cells

Adult spleen cells from C57BL.Ige mice, which generally are resistant to in vitro tolerance induction in the B-cell compartment, became hyporesponsive (tolerant) when cultured with antigen in the presence of an anti-allotype serum. Both antigen and anti-delta had to be present for this effect, which was hapten-specific and did not occur in C57BL/L mice, which lack the Ig5-1 allotype of the delta-chain detected in this system. Preculture with anti-mu serum plus antigen, in contrast, did not cause tolerance induction in adult spleen B cells of either strain. These results suggest that the surface IgD may act as a failsafe receptor to prevent tolerance induction in adult B cells. Tolerance studies with spleen cells from mice with markedly reduced numbers of IgD+ve cells, because of regimen of repeated injections of anti-delta serum beginning at birth (delta-suppressed mice), confirmed the importance of membrane IgD in preventing tolerance, because such delta-suppressed mice were hypersusceptible to tolerance by antigen alone. Inasmuch as immature B cells lack IgD on their surface, these studies suggest that acquisition of IgD is an important maturational step in the ability of murine B cells to discriminate tolerogenic and immunogenic signals.

CD74 induces TAp63 expression leading to B-cell survival

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4303-4311 ◽  
Author(s):  
Frida Lantner ◽  
Diana Starlets ◽  
Yael Gore ◽  
Liat Flaishon ◽  
Ayala Yamit-Hezi ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Cell Survival ◽  
Target Genes ◽  
Quiescent State ◽  
Cell Repertoire ◽  
Surface Receptors ◽  
B Cell Survival

Most mature follicular B cells circulate within the periphery in a quiescent state, without actively contributing to an acute immune response. Lasting B-cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. We recently demonstrated that cell surface CD74 controls mature B-cell survival. Stimulation of cell surface CD74 leads to NF-κB activation, which enables entry of the stimulated B cells into the S phase, induction of DNA synthesis, and cell division, and augments the expression of survival genes. In the present study, we investigated CD74 target genes to determine the identities of the molecules whose expression is modulated by CD74, thereby regulating B-cell survival. We report that CD74 activates the p65 member of the NF-κB family, which in turn up-regulates the expression of p53-related TAp63 proteins. TAp63 then binds and transactivates the Bcl-2gene and induces the production of Bcl-2 protein, thereby providing the cells with increased survival capacity. Thus, the CD74/NF-κB/TAp63 axis defines a novel antiapoptotic pathway in mature B cells, resulting in the shaping of both the B-cell repertoire and the immune response.

scholarly journals Multimodal repertoire analysis unveils B cell biology in health and immune-mediated diseases

2022 ◽  
Author(s):  
Mineto Ota ◽  
Masahiro Nakano ◽  
Yasuo Nagafuchi ◽  
Satomi Kobayashi ◽  
Hiroaki Hatano ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Biology ◽  
Memory B Cells ◽  
Dependent Manner ◽  
Cell Repertoire ◽  
Repertoire Analysis ◽  
Immune Mediated ◽  
B Cell Subsets

Despite involvement of B cells in the pathogenesis of immune-mediated diseases, biological mechanisms underlying their function are scarcely understood. To overcome this gap, comprehensive analysis of the B cell repertoire is essential. Here, we cataloged and investigated the repertoire of five B cell subsets from 595 cases under immune-mediated diseases and health. CDR-H3 length among naive B cells was shortened among autoimmune diseases in an interferon signature-dependent manner. VDJ gene usage was skewed especially in plasmablasts and unswitched-memory B cells of systemic lupus erythematosus patients with frequent usage of VDJ genes used mainly in naive B cells and not unswitched-memory B cells of healthy controls. We developed a scoring system for this skewing, and it correlated with peripheral helper T cell transcriptomic signatures and disease activity and decreased after belimumab treatment. Moreover, genetic association analysis identified three molecules possibly involved in somatic hyper-mutation processes in humans. Our multimodal repertoire analysis brings new insights to B cell biology.

scholarly journals A role for gut-associated lymphoid tissue in shaping the human B cell repertoire

2013 ◽  
Vol 210 (9) ◽  
pp. 1665-1674 ◽  
Author(s):  
Anna Vossenkämper ◽  
Paul A. Blair ◽  
Niloufar Safinia ◽  
Louise D. Fraser ◽  
Lisa Das ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Lymphoid Tissue ◽  
Plasma Cells ◽  
Cell Subset ◽  
Cell Repertoire ◽  
Human B Cells ◽  
B Cell Repertoire ◽  
Immature B Cells

We have tracked the fate of immature human B cells at a critical stage in their development when the mature B cell repertoire is shaped. We show that a major subset of bone marrow emigrant immature human B cells, the transitional 2 (T2) B cells, homes to gut-associated lymphoid tissue (GALT) and that most T2 B cells isolated from human GALT are activated. Activation in GALT is a previously unknown potential fate for immature human B cells. The process of maturation from immature transitional B cell through to mature naive B cell includes the removal of autoreactive cells from the developing repertoire, a process which is known to fail in systemic lupus erythematosus (SLE). We observe that immature B cells in SLE are poorly equipped to access the gut and that gut immune compartments are depleted in SLE. Thus, activation of immature B cells in GALT may function as a checkpoint that protects against autoimmunity. In healthy individuals, this pathway may be involved in generating the vast population of IgA plasma cells and also the enigmatic marginal zone B cell subset that is poorly understood in humans.

scholarly journals Autocrine Secretion of Interferon γ Negatively Regulates Homing of Immature B Cells

2000 ◽  
Vol 192 (9) ◽  
pp. 1381-1388 ◽  
Author(s):  
Liat Flaishon ◽  
Rami Hershkoviz ◽  
Frida Lantner ◽  
Ofer Lider ◽  
Ronen Alon ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
Matrix Protein ◽  
Immune Cell ◽  
Interferon Γ ◽  
Extracellular Matrix Protein ◽  
Final Maturation ◽  
Immature B Cells ◽  
Immune Cell Migration

The mechanism by which immature B cells are sequestered from encountering foreign antigens present in lymph nodes or sites of inflammation, before their final maturation in the spleen, has not been elucidated. We show here that immature B cells fail to home to the lymph nodes. These cells can actively exclude themselves from antigen-enriched sites by downregulating their integrin-mediated adhesion to the extracellular matrix protein, fibronectin. This inhibition is mediated by interferon γ secretion. Perturbation of interferon γ activity in vivo leads to the homing of immature B cells to the lymph nodes. This is the first example of autocrine regulation of immune cell migration to sites of foreign antigen presentation.

scholarly journals The essential role played by B cells in supporting protective immunity againstTrichuris murisinfection is dependent on host genetic background and is independent of antibody

2019 ◽  
Author(s):  
Rinal Sahputra ◽  
Dominik Ruckerl ◽  
Kevin Couper ◽  
Werner Muller ◽  
Kathryn J Else
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Genetic Background ◽  
Protective Immunity ◽  
Essential Role ◽  
Accessory Cells ◽  
Ifn Γ ◽  
Anti Cd20

AbstractThis study investigates the role of B cells in immunity toTrichuris muris(T. muris) infection in two genetically distinct strains of mouse, using anti-CD20 monoclonal antibody (mAb) (Genentech-clone 5D2) to deplete B cells. Data is presented for the mouse strains: C57BL/6 and BALB/c, which mount mixed Th1/Th2, and highly polarised Th2 immune responses toT. muris, respectively. C57BL/6 mice receiving anti-CD20 treatment prior to and during, or anti-CD20 treatment that commenced two weeks post infection (p.i.), were susceptible toT. muris. Parasite-specific IgG1 antibodies were absent and Th2 type cytokines produced by mesenteric lymph nodes cells from mice receiving α-CD20 mAb treatment were significantly lower than produced by cells from isotype control treated mice. T follicular helper cells were also significantly reduced. Importantly, and in complete contrast, BALB/c mice were still able to expelT.murisin the absence of B cells, revealing that the essential role played by B cells in protective immunity was dependent on genetic background. To explore whether the important role played by the B cell in the protective immune response of C57BL/6 mice was in enabling strong Th2 responses in the presence of IFN-γ, IFN-γ was blocked using anti-IFN-γ mAb post B cell depletion. Depleting IFN-γ, in the absence of B cells restored worm expulsion in the absence of parasite-specific IgG1/IgG2c and partially rescued theT. murisspecific IL-13 response. Thus, our data suggest an important, antibody independent role for B cells in supporting Th2 type immune responses in mixed IFN-γ-rich Th1/Th2 immune response settings.Author summaryHow B cells contribute to protective immunity against parasitic nematodes remains unclear, with their importance as accessory cells under-explored. This study reveals that, on some genetic backgrounds, B cells are important for the expulsion ofT. murisby acting as accessory cells, supporting Th2 immune responses.

Circulating B-cell chronic lymphocytic leukemia cells display impaired migration to lymph nodes due to reduced LFA-1 expression

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3135-3135
Author(s):  
Tanja Nicole Hartmann ◽  
Valentin Grabovsky ◽  
Wei Wang ◽  
Petra Desch ◽  
Stefan Wollner ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Independent Manner ◽  
Immunodeficient Mice ◽  
Chemokine Cxcl12 ◽  
Rapid Activation

Abstract Homing to secondary lymphoid organs and re-entry to bone marrow (BM) are central aspects of leukemic pathophysiology. We investigated the roles of the two major lymphocyte integrins LFA-1 and VLA-4 on B-cell chronic lymphocytic leukaemia (CLL) cells in these processes. We found that CLL cells expressed significantly reduced LFA-1 due to low beta2 integrin transcripts and displayed diminished adhesiveness to ICAM-1-expressing endothelium in vitro. VLA-4 expression was heterogenous but underwent rapid activation by the BM chemokine CXCL12. Nevertheless, CLL cells failed to transmigrate across VCAM-1, ICAM-1 and CXCL12 expressing endothelium due to their deficient LFA-1 expression. Furthermore, when injected into tail veins of immunodeficient mice, normal B cells rapidly homed to lymph nodes (LNs) in a LFA-1 dependent manner whereas CLL cells did not. CLL alike normal B lymphocytes used VLA-4 rather than LFA-1 to reenter the BM. In contrast, both normal and CLL B cells homed to mice spleen in an LFA-1- and VLA-4-independent manner. Our results suggest that CLL cells are deficient in LFA-1-dependent trafficking to LNs but residual subsets can still re-enter the BM. Integrin blocking could be therefore an efficient strategy to prevent circulating CLL cells from reaching prosurvival niches in LNs and BM and directing these cells to the spleen.

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