T cell interactions with B cells during germinal center formation, a three‐step model

Abstract B7-H2, which is expressed constitutively on B cells and binds the inducible costimulator (ICOS) on antigen-activated T cells, is a member of the B7 family of costimulatory ligands. We have inactivated B7-H2 in the mouse. B7-H2–/– mice generate normal populations of B and T cells in their various lymphoid organs but have lower basal levels of heavy chain class–switched antibodies in their sera. These mice are able to mount normal immune responses to both type I and type II T-cell–independent antigens. However, their pattern of responses to a T-cell–dependent antigen is altered, with greatly reduced production of antigen-specific heavy chain class–switched antibodies, the levels of which could not be elevated even with repeated immunizations. This suggests a critical role for B7-H2 in the recall phases of the immune response. Germinal center formation is also impaired in the mutant mice. While B cells from the mutant mice could response normally to anti-IgM, anti-CD40, and lipopolysaccharide stimulation, the production of T-helper–type II cytokines such as interleukin-4 (IL-4) and IL-10 by primed CD4+ T cells from mutant mice were reduced. This indicated that the defects in humoral responses and germinal center formation in B7-H2–deficient mice are due to the lack of T-cell–mediated help to the B cells. Hence, B7-H2 on B cells is important for recruiting T-cell help via its interaction with ICOS and plays a critical role in costimulating humoral immune responses.

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Bach2 deficiency leads autoreactive B cells to produce IgG autoantibodies and induce lupus through a T cell-dependent extrafollicular pathway

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0352-x ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-13 ◽

Cited By ~ 7

Author(s):

Eunkyeong Jang ◽

Un Kyo Kim ◽

Kiseok Jang ◽

Young Soo Song ◽

Ji-Young Cha ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Lupus Erythematosus ◽

Germinal Center ◽

Class Switch Recombination ◽

Helper T Cells ◽

Autoreactive B Cells ◽

Class Switch ◽

Germinal Center Formation

AbstractClass-switched IgG autoantibodies but not unswitched IgM autoantibodies play a crucial role in the development of systemic lupus erythematosus (SLE). Bach2 is known to be essential for class switch recombination of Ig genes, but recent genomic and clinical studies have suggested an association of Bach2 deficiency with SLE. This study was undertaken to examine the mechanism by which Bach2 regulates the development of SLE. Despite defects in Ig class switch recombination and germinal center formation when actively immunized, Bach2−/− mice spontaneously accumulated IgG autoantibody-secreting cells without germinal center reactions in a regulatory T cell-independent manner, and this phenomenon was accompanied by manifestations akin to SLE. Transcriptome analyses revealed that Bach2 regulated the expression of genes related to germinal center formation and SLE pathogenesis in B cells. B cell-specific deletion of Bach2 was sufficient to impair the development of germinal center B cells but insufficient to promote the production of IgG autoantibodies. Bach2 deficiency caused CD4+ T cells to overexpress Icos and differentiate into extrafollicular helper T cells in a cell-autonomous manner. These findings suggest that Bach2-deficient autoreactive B cells preferentially react at extrafollicular sites to give rise to IgG class-switched pathogenic plasma cells and that this effect requires the help of Bach2-Icoshi helper T cells. Thus, the cell-autonomous roles of Bach2 in B cells and in their cognate CD4+ T cells are required to maintain self-tolerance against SLE.

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B cell function in mice transgenic for mCTLA4-H gamma 1: lack of germinal centers correlated with poor affinity maturation and class switching despite normal priming of CD4+ T cells.

Journal of Experimental Medicine ◽

10.1084/jem.179.3.819 ◽

1994 ◽

Vol 179 (3) ◽

pp. 819-830 ◽

Cited By ~ 94

Author(s):

P Lane ◽

C Burdet ◽

S Hubele ◽

D Scheidegger ◽

U Müller ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Transgenic Mice ◽

B Cell ◽

Germinal Center ◽

Cd4 T Cells ◽

Class Switching ◽

T Cell Help ◽

Germinal Center Formation

This report outlines the B cell phenotype of transgenic mice that overexpresses the mouse CTLA-4-human gamma 1 (mCTLA4-H gamma 1) protein. Despite the fact that these mice prime CD4+ T cells (Ronchese, F., B. Housemann, S. Hubele, and P. Lane. 1994. J. Exp. Med. 179:809), antibody responses to T-dependent antigens are severely impaired. In contrast, T-independent responses are normal which suggests mCTLA4-H gamma 1 does not act directly on B cells, but acts indirectly by impairing T cell help. The impaired antibody defect is associated with impaired class switching, with low total immunoglobulin (Ig)G and antigen-specific IgG responses, and an absence of germinal center formation in spleen and lymph nodes but not gut-associated tissues. The defective germinal center formation is associated with a reduction in the degree of somatic mutation in hybridomas made from transgenic mice in comparison with those made from normal mice. It seems likely that mCTLA4-H gamma 1 exerts its effect by blocking an interaction between T and B cells that induce T cell help for B cells.

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Disruption of the Bcl6 Gene Results in an Impaired Germinal Center Formation

Journal of Experimental Medicine ◽

10.1084/jem.186.3.439 ◽

1997 ◽

Vol 186 (3) ◽

pp. 439-448 ◽

Cited By ~ 262

Author(s):

Tetsuya Fukuda ◽

Takehiko Yoshida ◽

Seiji Okada ◽

Masahiko Hatano ◽

Tohru Miki ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

Bone Marrow Cells ◽

Chromosomal Translocation ◽

Lymphoid Tissues ◽

Deficient Mice ◽

Germinal Center Formation

The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, and its products are expressed highly in germinal center (GC) B cells. To investigate the function of Bcl6 in lymphocytes, we have generated RAG1-deficient mice reconstituted with bone marrow cells from Bcl6-deficient mice (Bcl6−/−RM). Lymphogenesis in primary lymphoid tissues of Bcl6−/−RM is normal, and Bcl6−/−RM produced control levels of primary IgG1 antibodies specific to T cell–dependent antigens. However, GCs were not found in these mice. This defect was mainly due to the abnormalities of B cells. Therefore, Bcl6 is essential for the differentiation of GC B cells.

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Faculty Opinions recommendation of IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726281756.793521197 ◽

2016 ◽

Author(s):

Roberto Caricchio ◽

Stefania Gallucci

Keyword(s):

B Cells ◽

Germinal Center ◽

Stat1 Signaling ◽

Ifn Γ ◽

Germinal Center Formation

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Superantigens initiate cognate CD4+ T cell/ B cell interactions leading to early activation and proliferation of B cells

European Journal of Immunology ◽

10.1002/eji.1830250920 ◽

1995 ◽

Vol 25 (9) ◽

pp. 2539-2543 ◽

Cited By ~ 9

Author(s):

Reem Al-Daccak ◽

Bassam Damaj ◽

Paul H. Naccache ◽

Walid Mourad

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Interactions ◽

Cd4 T Cell ◽

Early Activation

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Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway

Journal of Experimental Medicine ◽

10.1084/jem.185.12.2121 ◽

1997 ◽

Vol 185 (12) ◽

pp. 2121-2131 ◽

Cited By ~ 84

Author(s):

Robbert van der Voort ◽

Taher E.I. Taher ◽

Robert M.J. Keehnen ◽

Lia Smit ◽

Martijn Groenink ◽

...

Keyword(s):

Cell Adhesion ◽

T Cell ◽

B Cells ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Tyrosine Kinase ◽

B Cell ◽

Germinal Center ◽

Scatter Factor ◽

Hepatocyte Growth

T cell–dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met–encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38+CD77+ tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.

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Somatic diversification in the absence of antigen-driven responses is the hallmark of the IgM+IgD+CD27+ B cell repertoire in infants

Journal of Experimental Medicine ◽

10.1084/jem.20071555 ◽

2008 ◽

Vol 205 (6) ◽

pp. 1331-1342 ◽

Cited By ~ 108

Author(s):

Sandra Weller ◽

Maria Mamani-Matsuda ◽

Capucine Picard ◽

Corinne Cordier ◽

Damiana Lecoeuche ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Immune Responses ◽

Germinal Center ◽

Early Stage ◽

Cell Repertoire ◽

Very Young Children ◽

B Cell Repertoire ◽

Somatic Diversification ◽

The Many

T cell–dependent immune responses develop soon after birth, whereas it takes 2 yr for humans to develop T cell–independent responses. We used this dissociation to analyze the repertoire diversification of IgM+IgD+CD27+ B cells (also known as “IgM memory” B cells), comparing these cells with switched B cells in children <2 yr of age, with the aim of determining whether these two subsets are developmentally related. We show that the repertoire of IgM+IgD+CD27+ B cells in the spleen and blood displays no sign of antigen-driven activation and expansion on H-CDR3 spectratyping, despite the many antigenic challenges provided by childhood vaccinations. This repertoire differed markedly from those of switched B cells and splenic germinal center B cells, even at the early stage of differentiation associated with μ heavy chain expression. These data provide evidence for the developmental diversification of IgM+IgD+CD27+ B cells, at least in very young children, outside of T cell–dependent and –independent immune responses.

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Germinal center B cell development has distinctly regulated stages completed by disengagement from T cell help

eLife ◽

10.7554/elife.19552 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 20

Author(s):

Ting-ting Zhang ◽

David G Gonzalez ◽

Christine M Cote ◽

Steven M Kerfoot ◽

Shaoli Deng ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

B Cell Differentiation ◽

B Cell Maturation ◽

Germinal Center B Cell ◽

T Cell Help ◽

Dose Dependent

To reconcile conflicting reports on the role of CD40 signaling in germinal center (GC) formation, we examined the earliest stages of murine GC B cell differentiation. Peri-follicular GC precursors first expressed intermediate levels of BCL6 while co-expressing the transcription factors RelB and IRF4, the latter known to repress Bcl6 transcription. Transition of GC precursors to the BCL6hi follicular state was associated with cell division, although the number of required cell divisions was immunogen dose dependent. Potentiating T cell help or CD40 signaling in these GC precursors actively repressed GC B cell maturation and diverted their fate towards plasmablast differentiation, whereas depletion of CD4+ T cells promoted this initial transition. Thus while CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, transition to the BCL6hi follicular state is promoted by a regional and transient diminution of T cell help.

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