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Article: Non-Canonical NF-κB Signaling Initiated by BAFF Influences B Cell Biology at Multiple Junctures.

Gardam, Sandra / Brink, Robert

2014 Volume 4, Page(s) 509

Abstract: It has been more than a decade since it was recognized that the nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) transcription factor family was activated by two distinct pathways: the canonical pathway involving NF-κB1 and the ... ...

Abstract	It has been more than a decade since it was recognized that the nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) transcription factor family was activated by two distinct pathways: the canonical pathway involving NF-κB1 and the non-canonical pathway involving NF-κB2. During this time a great deal of evidence has been amassed on the ligands and receptors that activate these pathways, the cytoplasmic adapter molecules involved in transducing the signals from receptors to nucleus, and the resulting physiological outcomes within body tissues. In contrast to NF-κB1 signaling, which can be activated by a wide variety of receptors, the NF-κB2 pathway is typically only activated by a subset of receptor and ligand pairs belonging to the tumor necrosis factor (TNF) family. Amongst these is B cell activating factor of the TNF family (BAFF) and its receptor BAFFR. Whilst BAFF is produced by many cell types throughout the body, BAFFR expression appears to be restricted to the hematopoietic lineage and B cells in particular. For this reason, the main physiological outcomes of BAFF mediated NF-κB2 activation are confined to B cells. Indeed BAFF mediated NF-κB2 signaling contributes to peripheral B cell survival and maturation as well as playing a role in antibody responses and long term maintenance plasma cells. Thus the importance BAFF and NF-κB2 permeates the entire B cell lifespan and impacts on this important component of the immune system in a variety of ways.
Language	English
Publishing date	2014-01-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2013.00509
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Article ; Online: The kinase NIK as a therapeutic target in multiple myeloma.

Gardam, Sandra / Beyaert, Rudi

Expert opinion on therapeutic targets

2011 Volume 15, Issue 2, Page(s) 207–218

Abstract: Introduction: Multiple myeloma (MM) is a neoplasm derived from B lymphocytes and often results in uncontrolled clonal expansion of antibody-secreting cells. While current treatments are able to prolong survival, MM remains incurable. Excessive NF-κB ... ...

Abstract	Introduction: Multiple myeloma (MM) is a neoplasm derived from B lymphocytes and often results in uncontrolled clonal expansion of antibody-secreting cells. While current treatments are able to prolong survival, MM remains incurable. Excessive NF-κB activity in MM contributes to tumor progression and survival. Areas covered: The contribution of NF-κB-inducing kinase (NIK) to alternative NF-κB signaling, where it is the key kinase, and classical NF-κB signaling. Modulation of NIK by natural and chemical factors and current and potential therapies for MM that target NIK. Expert opinion: Mutations affecting the activation of NIK have been identified in MM samples and cell lines, suggesting that NIK may be an important target for therapy of MM. NIK contributes to activation of both NF-κB pathways in MM, giving us the opportunity to limit two pathways contributing to oncogenic survival with a single therapeutic. Many of the mutations identified in MM cells result in the same outcome, hyperactive NIK, thus a single therapeutic may be effective in many patients even though they carry differing mutations. As NIK appears only to activate classical NF-κB when overexpressed, and in normal cells NIK levels are usually low, it is possible that therapeutics designed to limit the amount of NIK may not produce serious side effects in healthy cells.
MeSH term(s)	B-Lymphocytes/pathology ; B-Lymphocytes/physiology ; Humans ; Molecular Targeted Therapy ; Multiple Myeloma/drug therapy ; Multiple Myeloma/genetics ; Multiple Myeloma/metabolism ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; Transcriptional Activation ; NF-kappaB-Inducing Kinase
Chemical Substances	NF-kappa B ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2011-01-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2055208-7
ISSN	1744-7631 ; 1472-8222
ISSN (online)	1744-7631
ISSN	1472-8222
DOI	10.1517/14728222.2011.548861
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Article: XEDAR activates the non-canonical NF-κB pathway

Verhelst, Kelly / Gardam, Sandra / Borghi, Alice / Kreike, Marja / Carpentier, Isabelle / Beyaert, Rudi

Biochemical and biophysical research communications. 2015 Sept. 18, v. 465

2015

Abstract: Members of the tumor necrosis factor receptor (TNFR) superfamily are involved in a number of physiological and pathological responses by activating a wide variety of intracellular signaling pathways. The X-linked ectodermal dysplasia receptor (XEDAR; ... ...

Abstract	Members of the tumor necrosis factor receptor (TNFR) superfamily are involved in a number of physiological and pathological responses by activating a wide variety of intracellular signaling pathways. The X-linked ectodermal dysplasia receptor (XEDAR; also known as EDA2R or TNFRSF27) is a member of the TNFR superfamily that is highly expressed in ectodermal derivatives during embryonic development and binds to ectodysplasin-A2 (EDA-A2), a member of the TNF family that is encoded by the anhidrotic ectodermal dysplasia (EDA) gene. Although XEDAR was first described in the year 2000, its function and molecular mechanism of action is still largely unclear. XEDAR has been reported to activate canonical nuclear factor κB (NF-κB) signaling and mitogen-activated protein (MAP) kinases. Here we report that XEDAR is also able to trigger the non-canonical NF-κB pathway, characterized by the processing of p100 (NF-κB2) into p52, followed by nuclear translocation of p52 and RelB. We provide evidence that XEDAR-induced p100 processing relies on the binding of XEDAR to TRAF3 and TRAF6, and requires the kinase activity of NIK and IKKα. We also show that XEDAR stimulation results in NIK accumulation and that p100 processing is negatively regulated by TRAF3, cIAP1 and A20.
Keywords	embryogenesis ; genes ; mechanism of action ; phosphotransferases (kinases) ; signal transduction ; transcription factor NF-kappa B ; tumor necrosis factors
Language	English
Dates of publication	2015-0918
Size	p. 275-280.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2015.08.019
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Article ; Online: XEDAR activates the non-canonical NF-κB pathway.

Verhelst, Kelly / Gardam, Sandra / Borghi, Alice / Kreike, Marja / Carpentier, Isabelle / Beyaert, Rudi

Biochemical and biophysical research communications

2015 Volume 465, Issue 2, Page(s) 275–280

Abstract	Members of the tumor necrosis factor receptor (TNFR) superfamily are involved in a number of physiological and pathological responses by activating a wide variety of intracellular signaling pathways. The X-linked ectodermal dysplasia receptor (XEDAR; also known as EDA2R or TNFRSF27) is a member of the TNFR superfamily that is highly expressed in ectodermal derivatives during embryonic development and binds to ectodysplasin-A2 (EDA-A2), a member of the TNF family that is encoded by the anhidrotic ectodermal dysplasia (EDA) gene. Although XEDAR was first described in the year 2000, its function and molecular mechanism of action is still largely unclear. XEDAR has been reported to activate canonical nuclear factor κB (NF-κB) signaling and mitogen-activated protein (MAP) kinases. Here we report that XEDAR is also able to trigger the non-canonical NF-κB pathway, characterized by the processing of p100 (NF-κB2) into p52, followed by nuclear translocation of p52 and RelB. We provide evidence that XEDAR-induced p100 processing relies on the binding of XEDAR to TRAF3 and TRAF6, and requires the kinase activity of NIK and IKKα. We also show that XEDAR stimulation results in NIK accumulation and that p100 processing is negatively regulated by TRAF3, cIAP1 and A20.
MeSH term(s)	DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Ectodysplasins/genetics ; Ectodysplasins/metabolism ; Gene Expression Regulation ; HEK293 Cells ; Humans ; I-kappa B Kinase/genetics ; I-kappa B Kinase/metabolism ; Inhibitor of Apoptosis Proteins/genetics ; Inhibitor of Apoptosis Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Mitogen-Activated Protein Kinases/genetics ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B p52 Subunit/genetics ; NF-kappa B p52 Subunit/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein Binding ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; TNF Receptor-Associated Factor 3/genetics ; TNF Receptor-Associated Factor 3/metabolism ; TNF Receptor-Associated Factor 6/genetics ; TNF Receptor-Associated Factor 6/metabolism ; Tumor Necrosis Factor alpha-Induced Protein 3 ; Xedar Receptor/genetics ; Xedar Receptor/metabolism ; NF-kappaB-Inducing Kinase
Chemical Substances	DNA-Binding Proteins ; EDA protein, human ; EDA2R protein, human ; Ectodysplasins ; Inhibitor of Apoptosis Proteins ; Intracellular Signaling Peptides and Proteins ; NF-kappa B p52 Subunit ; Nuclear Proteins ; TNF Receptor-Associated Factor 3 ; TNF Receptor-Associated Factor 6 ; TRAF3 protein, human ; Xedar Receptor ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; CHUK protein, human (EC 2.7.11.10) ; I-kappa B Kinase (EC 2.7.11.10) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; TNFAIP3 protein, human (EC 3.4.19.12) ; Tumor Necrosis Factor alpha-Induced Protein 3 (EC 3.4.19.12)
Language	English
Publishing date	2015-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2015.08.019
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Article ; Online: Lineage-specific transgene expression in hematopoietic cells using a Cre-regulated retroviral vector.

Turner, Vivian M / Gardam, Sandra / Brink, Robert

Journal of immunological methods

2010 Volume 360, Issue 1-2, Page(s) 162–166

Abstract: Transduction of bone marrow stem cells with retroviral expression vectors represents a cheaper and more rapid alternative to conventional transgenesis for studies of in vivo gene function. However, achieving tissue-specific expression of genes inserted ... ...

Abstract	Transduction of bone marrow stem cells with retroviral expression vectors represents a cheaper and more rapid alternative to conventional transgenesis for studies of in vivo gene function. However, achieving tissue-specific expression of genes inserted into retroviral vectors is notoriously difficult. We have developed a single tri-cistronic retroviral vector (MG(f)I4) that facilitates Cre-dependent, lineage-specific gene expression within hematopoietic cells. Bone marrow stem cells transduced with MG(f)I4 co-express a loxP-flanked (floxed) eGFP cDNA together with truncated human CD4 (hCD4Delta). Open reading frames (ORFs) cloned between these two cDNAs are not constitutively translated but are activated upon Cre-mediated removal of the eGFP cDNA. Mice reconstituted with transduced bone marrow stem cells obtained from Cd19-Cre, Cr2-Cre or Lck-Cre, donors were shown to specifically express an ORF insert in the appropriate lymphocyte subsets. Cells that had activated ORF expression were identifiable by transition from a GFP+, hCD4+ to a GFP(-), hCD4+ phenotype. The use of this novel vector in conjunction with the wide range of well-characterized Cre-transgenic lines will be a versatile tool for exploring gene function within the immune system. In particular, this approach will provide a convenient way to test the functional significance of naturally occurring genetic mutations linked to human disease.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Antigens, CD19/genetics ; Antigens, CD19/metabolism ; Bone Marrow Cells/pathology ; Bone Marrow Transplantation ; CD4 Antigens/genetics ; CD4 Antigens/metabolism ; Cell Lineage/genetics ; Genetic Vectors ; Green Fluorescent Proteins/genetics ; Hematopoietic Stem Cells/immunology ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/pathology ; Humans ; Integrases/genetics ; Integrases/metabolism ; Lymphocyte Subsets/immunology ; Lymphocyte Subsets/metabolism ; Lymphocyte Subsets/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Organ Specificity/genetics ; Organ Specificity/immunology ; Receptors, Complement 3d/genetics ; Receptors, Complement 3d/metabolism ; Retroviridae/genetics ; Sequence Deletion
Chemical Substances	Adaptor Proteins, Signal Transducing ; Antigens, CD19 ; CD4 Antigens ; Receptors, Complement 3d ; Sh2d2a protein, mouse ; Green Fluorescent Proteins (147336-22-9) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
Language	English
Publishing date	2010-08-31
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120142-6
ISSN	1872-7905 ; 0022-1759
ISSN (online)	1872-7905
ISSN	0022-1759
DOI	10.1016/j.jim.2010.06.007
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Article ; Online: TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15.

Villanueva, Jeanette E / Malle, Elisabeth K / Gardam, Sandra / Silveira, Pablo A / Zammit, Nathan W / Walters, Stacey N / Brink, Robert / Grey, Shane T

European journal of immunology

2015 Volume 45, Issue 6, Page(s) 1820–1831

Abstract: In this study, a critical and novel role for TNF receptor (TNFR) associated factor 2 (TRAF2) is elucidated for peripheral CD8(+) T-cell and NKT-cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ∼40% reduction in effector ... ...

Abstract	In this study, a critical and novel role for TNF receptor (TNFR) associated factor 2 (TRAF2) is elucidated for peripheral CD8(+) T-cell and NKT-cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ∼40% reduction in effector memory and ∼50% reduction in naïve CD8(+) T-cell subsets. IL-15-dependent populations were reduced further, as TRAF2TKO mice displayed a marked ∼70% reduction in central memory CD8(+) CD44(hi) CD122(+) T cells and ∼80% decrease in NKT cells. TRAF2TKO CD8(+) CD44(hi) T cells exhibited impaired dose-dependent proliferation to exogenous IL-15. In contrast, TRAF2TKO CD8(+) T cells proliferated normally to anti-CD3 and TRAF2TKO CD8(+) CD44(hi) T cells exhibited normal proliferation to exogenous IL-2. TRAF2TKO CD8(+) T cells expressed normal levels of IL-15-associated receptors and possessed functional IL-15-mediated STAT5 phosphorylation, however TRAF2 deletion caused increased AKT activation. Loss of CD8(+) CD44(hi) CD122(+) and NKT cells was mechanistically linked to an inability to respond to IL-15. The reduced CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell populations in TRAF2TKO mice were rescued in the presence of high dose IL-15 by IL-15/IL-15Rα complex administration. These studies demonstrate a critical role for TRAF2 in the maintenance of peripheral CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell homeostasis by modulating sensitivity to T-cell intrinsic growth factors such as IL-15.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/physiology ; Cellular Microenvironment ; Cytokines/pharmacology ; Female ; Gene Expression ; Homeostasis ; Immunologic Memory ; Immunophenotyping ; Interleukin-15/pharmacology ; Lymphocyte Count ; Lymphopenia/genetics ; Lymphopenia/immunology ; Lymphopenia/metabolism ; Male ; Mice ; Mice, Knockout ; NF-kappa B/metabolism ; Natural Killer T-Cells/drug effects ; Natural Killer T-Cells/physiology ; Phenotype ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Interleukin-15/genetics ; Receptors, Interleukin-15/metabolism ; Signal Transduction ; T-Lymphocyte Subsets/drug effects ; T-Lymphocyte Subsets/physiology ; TNF Receptor-Associated Factor 2/genetics ; TNF Receptor-Associated Factor 2/metabolism ; TNF Receptor-Associated Factor 3/genetics ; TNF Receptor-Associated Factor 3/metabolism
Chemical Substances	Cytokines ; Interleukin-15 ; NF-kappa B ; Receptors, Interleukin-15 ; TNF Receptor-Associated Factor 2 ; TNF Receptor-Associated Factor 3 ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2015-06
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201445416
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Article ; Online: TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor.

Gardam, Sandra / Sierro, Frederic / Basten, Antony / Mackay, Fabienne / Brink, Robert

Immunity

2008 Volume 28, Issue 3, Page(s) 391–401

Abstract: Tumor necrosis factor receptor-associated factors 2 and 3 (TRAF2 and TRAF3) were shown to function in a cooperative and nonredundant manner to suppress nuclear factor-kappaB2 (NF-kappaB2) activation, gene expression, and survival in mature B cells. In ... ...

Abstract	Tumor necrosis factor receptor-associated factors 2 and 3 (TRAF2 and TRAF3) were shown to function in a cooperative and nonredundant manner to suppress nuclear factor-kappaB2 (NF-kappaB2) activation, gene expression, and survival in mature B cells. In the absence of this suppressive activity, B cells developed independently of the obligatory B cell survival factor, BAFF (B cell-activating factor of the tumor necrosis factor family). However, deletion of either TRAF2 or TRAF3 from the T cell lineage did not promote T cell survival, despite causing extensive NF-kappaB2 activation. This constitutive, lineage-specific suppression of B cell survival by TRAF2 and TRAF3 determines the requirement for BAFF to sustain B cell development in vivo. Binding of BAFF to BAFF receptor reversed TRAF2-TRAF3-mediated suppression of B cell survival by triggering the depletion of TRAF3 protein. This process was TRAF2 dependent, revealing dual roles for TRAF2 in regulating B cell homeostasis.
MeSH term(s)	Animals ; B-Cell Activation Factor Receptor/immunology ; B-Cell Activation Factor Receptor/metabolism ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; Cell Differentiation/immunology ; Cell Survival/immunology ; Flow Cytometry ; Gene Expression ; Gene Expression Profiling ; Mice ; Mice, Transgenic ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Signal Transduction/immunology ; TNF Receptor-Associated Factor 2/immunology ; TNF Receptor-Associated Factor 2/metabolism ; TNF Receptor-Associated Factor 3/immunology ; TNF Receptor-Associated Factor 3/metabolism
Chemical Substances	B-Cell Activation Factor Receptor ; TNF Receptor-Associated Factor 2 ; TNF Receptor-Associated Factor 3
Language	English
Publishing date	2008-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2008.01.009
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Article: In vivo control of B-cell survival and antigen-specific B-cell responses

Chan, Tyani D / Gardam, Sandra / Gatto, Dominique / Turner, Vivian M / Silke, John / Brink, Robert

Immunological reviews. 2010 Sept., v. 237, no. 1

2010

Abstract: Targeted modification of the mouse genome provides the capability to manipulate complex physiological processes in a precise and controlled manner. Investigation of B-lymphocyte biology has benefited not only from the targeted modification of genes ... ...

Abstract	Targeted modification of the mouse genome provides the capability to manipulate complex physiological processes in a precise and controlled manner. Investigation of B-lymphocyte biology has benefited not only from the targeted modification of genes controlling B-cell survival and responsiveness, but also from the manipulation of antigen specificity made possible by targeting endogenous immunoglobulin loci. In this review, we discuss recent results obtained from our laboratory using gene-targeted mouse models to investigate the in vivo regulation of B-cell survival and responsiveness. The control of BAFF-dependent survival signals by the TRAF2- and TRAF3-signaling proteins is discussed as is the potential involvement of these molecules in B-lineage malignancies. We also outline the development and use of the SWHEL model for analyzing antigen-specific B-cell responses in vivo. This includes insights into the control of early decision-making during T-dependent B-cell differentiation, the affinity maturation and plasma cell differentiation of germinal center B cells, and the identification of EBI2 as a key regulator of B-cell migration and differentiation.
Keywords	plasma cells
Language	English
Dates of publication	2010-09
Size	p. 90-103.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/j.1600-065X.2010.00942.x
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Article ; Online: In vivo control of B-cell survival and antigen-specific B-cell responses.

Chan, Tyani D / Gardam, Sandra / Gatto, Dominique / Turner, Vivian M / Silke, John / Brink, Robert

Immunological reviews

2010 Volume 237, Issue 1, Page(s) 90–103

Abstract	Targeted modification of the mouse genome provides the capability to manipulate complex physiological processes in a precise and controlled manner. Investigation of B-lymphocyte biology has benefited not only from the targeted modification of genes controlling B-cell survival and responsiveness, but also from the manipulation of antigen specificity made possible by targeting endogenous immunoglobulin loci. In this review, we discuss recent results obtained from our laboratory using gene-targeted mouse models to investigate the in vivo regulation of B-cell survival and responsiveness. The control of BAFF-dependent survival signals by the TRAF2- and TRAF3-signaling proteins is discussed as is the potential involvement of these molecules in B-lineage malignancies. We also outline the development and use of the SW(HEL) model for analyzing antigen-specific B-cell responses in vivo. This includes insights into the control of early decision-making during T-dependent B-cell differentiation, the affinity maturation and plasma cell differentiation of germinal center B cells, and the identification of EBI2 as a key regulator of B-cell migration and differentiation.
MeSH term(s)	Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; Cell Survival ; Germinal Center/cytology ; Germinal Center/immunology ; Mice ; Models, Immunological ; TNF Receptor-Associated Factor 2/metabolism ; TNF Receptor-Associated Factor 3/metabolism
Chemical Substances	TNF Receptor-Associated Factor 2 ; TNF Receptor-Associated Factor 3
Language	English
Publishing date	2010-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/j.1600-065X.2010.00942.x
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Article: Altered migration, recruitment, and somatic hypermutation in the early response of marginal zone B cells to T cell-dependent antigen.

Phan, Tri Giang / Gardam, Sandra / Basten, Antony / Brink, Robert

Journal of immunology (Baltimore, Md. : 1950)

2004 Volume 174, Issue 8, Page(s) 4567–4578

Abstract: The early responses of follicular (Fo) and marginal zone (MZ) B cells to T cell-dependent Ag were compared using anti-hen egg lysozyme (HEL+) B cells capable of class switch recombination and somatic hypermutation (SHM). Purified CD21/(35int)CD23high Fo ... ...

Abstract	The early responses of follicular (Fo) and marginal zone (MZ) B cells to T cell-dependent Ag were compared using anti-hen egg lysozyme (HEL+) B cells capable of class switch recombination and somatic hypermutation (SHM). Purified CD21/(35int)CD23high Fo and CD21/35(high)CD23low MZ splenic B cells from SW(HEL) Ig-transgenic mice were transferred into wild-type recipients and challenged with HEL-sheep RBC. Responding HEL+ B cells from both populations switched efficiently to IgG1, generated syndecan-1+ Ab-secreting cells, and exhibited equivalent rates of proliferation. However, the expansion of HEL+ MZ B cells lagged significantly behind that of HEL+ Fo B cells due to less efficient homing to the outer periarteriolar lymphatic sheath and reduced recruitment into the proliferative response. Despite the equivalent rates of class switch recombination, the onset of SHM was delayed in the MZ subset, indicating that these two activation-induced cytidine deaminase-dependent events are uncoupled in the early response of MZ B cells. Migration of HEL+ B cells into germinal centers coincided with the onset of SHM, occurring more rapidly with Fo vs MZ responders. These results are consistent with the concept that Fo and MZ B cells have evolved to specialize in T cell-dependent and T-independent responses respectively.
MeSH term(s)	Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/transplantation ; Base Sequence ; Cell Movement ; Chickens ; DNA/genetics ; Erythrocytes/immunology ; Immunoglobulin G/biosynthesis ; In Vitro Techniques ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Nude ; Mice, Transgenic ; Muramidase/immunology ; Sheep ; Somatic Hypermutation, Immunoglobulin ; T-Lymphocytes/immunology
Chemical Substances	Immunoglobulin G ; DNA (9007-49-2) ; Muramidase (EC 3.2.1.17)
Language	English
Publishing date	2004-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.174.8.4567
Database	MEDical Literature Analysis and Retrieval System OnLINE

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