Substrate stiffness regulates B-cell activation, proliferation, class switch, and T-cell-independent antibody responses in vivo

AbstractMigration and adhesion play critical roles in B cells, regulating recirculation between lymphoid organs, migration within lymphoid tissue and interaction with CD4+ T cells. However, there is limited knowledge of how B cells integrate chemokine receptor and integrin signaling with B cell activation to generate efficient humoral responses. Here we show that the WNK1 kinase, a regulator of migration and adhesion, is essential in B cells for T-dependent antibody responses. We demonstrate that WNK1 transduces signals from the BCR, CXCR5 and CD40, and using intravital imaging we show that WNK1 regulates migration of naive and activated B cells, and their interactions with T cells. Unexpectedly, we show that WNK1 is required for BCR- and CD40-induced proliferation, acting through the OXSR1 and STK39 kinases, and for efficient B cell-T cell collaboration in vivo. Thus, WNK1 is critical for humoral immune responses, by regulating B cell migration, adhesion and T cell-dependent activation.SummaryThe WNK1 kinase is essential in B cells for T-dependent antibody responses because it is activated by signaling from BCR, CXCR5 and CD40 and regulates B cell migration, adhesion, T-dependent activation, and differentiation into germinal center B cells and plasma cells.

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Antiviral Protection and Germinal Center Formation, But Impaired B Cell Memory in the Absence of CD19

Journal of Experimental Medicine ◽

10.1084/jem.188.1.145 ◽

1998 ◽

Vol 188 (1) ◽

pp. 145-155 ◽

Cited By ~ 49

Author(s):

Thomas Fehr ◽

Robert C. Rickert ◽

Bernhard Odermatt ◽

Jürgen Roes ◽

Klaus Rajewsky ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Antibody Responses ◽

B Cell Activation ◽

Protein Antigens ◽

Cell Memory ◽

B Cell Memory

Coligation of CD19, a molecule expressed during all stages of B cell development except plasmacytes, lowers the threshold for B cell activation with anti-IgM by a factor of 100. The cytoplasmic tail of CD19 contains nine tyrosine residues as possible phosphorylation sites and is postulated to function as the signal transducing element for complement receptor (CR)2. Generation and analysis of CD19 gene–targeted mice revealed that T cell–dependent (TD) antibody responses to proteinaceous antigens were impaired, whereas those to T cell–independent (TI) type 2 antigens were normal or even augmented. These results are compatible with earlier complement depletion studies and the postulated function of CD19. To analyze the role of CD19 in antiviral antibody responses, we immunized CD19−/− mice with viral antigens of TI-1, TI-2, and TD type. The effect of CD19 on TI responses was more dependent on antigen dose and replicative capacity than on antigen type. CR blocking experiments confirmed the role of CD19 as B cell signal transducer for complement. In contrast to immunization with protein antigens, infection of CD19−/− mice with replicating virus led to generation of specific germinal centers, which persisted for >100 d, whereas maintenance of memory antibody titers as well as circulating memory B cells was fully dependent on CD19. Thus, our study confirms a costimulatory role of CD19 on B cells under limiting antigen conditions and indicates an important role for B cell memory.

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Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation.

Journal of Experimental Medicine ◽

10.1084/jem.183.5.2303 ◽

1996 ◽

Vol 183 (5) ◽

pp. 2303-2312 ◽

Cited By ~ 141

Author(s):

K M Toellner ◽

A Gulbranson-Judge ◽

D R Taylor ◽

D M Sze ◽

I C MacLennan

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Messenger Rna ◽

Cell Activation ◽

Plasma Cells ◽

Cell Interaction ◽

Primary Response ◽

Antibody Responses

Immunoglobulin (Ig) class switch recombination is associated with the production and splicing of germline IgCH messenger RNA transcripts. Levels of gamma 1 transcripts in mouse spleen sections were assessed by semiquantitative analysis of reverse transcriptase polymerase chain reaction (PCR) products during primary and secondary antibody responses to chicken gamma globulin (CGG). This was correlated with the appearance of CGG-specific B cells and their growth and differentiation to plasma cells. After primary immunization with CGG, gamma 1 switch transcripts appeared after 4 d, peaked at a median of six times starting levels between 10 and 18 d after immunization, and returned to background levels before secondary immunization at 5 wk. By contrast, after secondary challenge with CGG, a sevenfold increase in transcripts occurs during the first d. The level again doubles by day 3, when it is six times that which is seen at the peak of the primary response. After day 4, there was a gradual decline over the next 2-3 wk. Within 12 h of secondary immunization, antigen-specific memory B cells appeared in the outer I zone and by 24 h entered S phase, presumably as a result of cognate interaction with primed T cells. Over the next few hours, they migrated to the edge of the red pulp, where they grew exponentially until the fourth day, when they synchronously differentiated to become plasma cells. The same pattern was seen for the migration, growth, and differentiation of virgin hapten-specific B cells when CGG-primed mice were challenged with hapten protein. The continued production of transcripts after day 3 indicates that switching also occurs in germinal centers, but in a relatively small proportion of their B cells. The impressive early production of switch transcripts during T cell-dependent antibody responses occurs in cells that are about to undergo massive clonal expansion. It is argued that Ig class switching at this time, which is associated with cognate T cell-B cell interaction in the T zone, has a major impact on the class and subclasses of Ig produced during the response.

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Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities

Blood ◽

10.1182/blood-2008-04-154682 ◽

2009 ◽

Vol 113 (11) ◽

pp. 2426-2433 ◽

Cited By ~ 125

Author(s):

Fouad Eddahri ◽

Sébastien Denanglaire ◽

Fabrice Bureau ◽

Rosanne Spolski ◽

Warren J. Leonard ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Interleukin 6 ◽

Cell Activation ◽

B Cell Activation ◽

Naive T Cells ◽

Naïve T Cells ◽

Helper Cells

Abstract The conditions leading to the activation/differentiation of T-helper (Th) cells dedicated for B-cell antibody production are still poorly characterized. We now demonstrate that interleukin-6 (IL-6) promotes the differentiation of naive T lymphocytes into helper cells able to promote B-cell activation and antibody secretion. IL-6–driven acquisition of B-cell help capacity requires expression of the signal transducer and activator of transcription 3 (STAT3), but not STAT4 or STAT6 transcription factors, suggesting that the ability to provide help to B cells is not restricted to a well-defined Th1 or Th2 effector population. T cell–specific STAT3-deficient mice displayed reduced humoral responses in vivo that could not be related to an altered expansion of CXCR5-expressing helper T cells. IL-6 was shown to promote IL-21 secretion, a cytokine that was similarly found to promote the differentiation of naive T cells into potent B-cell helper cells. Collectively, these data indicate that the ability to provide B-cell help is regulated by IL-6/IL-21 through STAT3 activation, independently of Th1, Th2, Th17, or follicular helper T cell (TFH) differentiation.

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Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function–Associated Antigen-1 and Kindlin-3

The Journal of Immunology ◽

10.4049/jimmunol.1402741 ◽

2015 ◽

Vol 195 (1) ◽

pp. 105-115 ◽

Cited By ~ 11

Author(s):

Vicky Louise Morrison ◽

Liisa M. Uotila ◽

Marc Llort Asens ◽

Terhi Savinko ◽

Susanna Carola Fagerholm

Keyword(s):

T Cell ◽

B Cell ◽

T Cell Activation ◽

Cell Activation ◽

Antibody Responses ◽

Leukocyte Function ◽

Cell Antibody

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Faculty Opinions recommendation of Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses.

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

10.3410/f.717955941.793460881 ◽

2012 ◽

Author(s):

Boris Reizis

Keyword(s):

Dendritic Cells ◽

T Cell ◽

B Cell ◽

Cell Activation ◽

Marginal Zone ◽

Antibody Responses ◽

B Cell Activation

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B cell dependence on and response to accessory signals in murine lupus strains.

Journal of Experimental Medicine ◽

10.1084/jem.157.6.1815 ◽

1983 ◽

Vol 157 (6) ◽

pp. 1815-1827 ◽

Cited By ~ 60

Author(s):

G J Prud'homme ◽

R S Balderas ◽

F J Dixon ◽

A N Theofilopoulos

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

B Cell Differentiation ◽

B Cell Activation ◽

Proliferation And Differentiation ◽

Cell Differentiation Factor

B cell hyperactivity, a feature common to all lupus-prone murine strains, may be caused by hyperresponsiveness to, overproduction of, or bypassing of certain signals required for B cell activation, proliferation, and differentiation. In this study, we have compared the responses of B cells from three lupus-prone strains of mice (BXSB males, MRL and NZB/W females) and normal strains in a number of assays for which two or more signals are required to obtain a response. In medium to low density cultures of B cells from BXSB and NZB/W but not MRL/l lupus mice, the cells' proliferation induced by bacterial lipopolysaccharide (LPS) or anti-mu antibody was much higher than that of B cells from normal controls. At low B cell density, polyclonal activation by these substances and subsequent Ig secretion were dependent on accessory signals present in supernatants of concanavalin A-treated normal lymphocytes (CAS) or on the MRL/l proliferating T cell-derived B cell differentiation factor (L-BCDF) in both lupus-prone and immunologically normal mice. However, the responses of B cells from BXSB and NZB/W, but not MRL/l, mice to these accessory signals were higher than those of normal mice. Ig synthesis by fresh B cells of BXSB and NZB/W mice cultured in the absence of mitogens but in the presence of CAS or L-BCDF was higher than by similar cells from other strains, suggesting an increased frequency of B cells activated in vivo in these two autoimmune strains of mice. The patterns of IgG subclass secretion in response to LPS (without added CAS or L-BCDF) were abnormal in all lupus strains, with a predominance of IgG2b and/or IgG2a and low levels of IgG3, contrary to normal B cells for which IgG3 synthesis predominated. However, IgG1 synthesis in vitro by autoimmune and normal B cells alike was highly dependent on T cell-derived soluble mediators. Antigen-specific responses to SRBC in vitro of B cells from all lupus strains, like those of B cells from normal strains, required a minimum of three signals (antigen, LPS, T cell-derived antigen nonspecific helper factors). Yet, once triggered, B cells of BXSB and NZB/W mice gave higher responses than those of the other strains. We conclude that B cells of lupus mice have signal requirements similar to those of normal mice. Nevertheless, B cells of BXSB and NZB/W, but not MRL/l, lupus mice hyperrespond or process some accessory signals abnormally.

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Non-Antigen-Specific B-Cell Activation following Murine Gammaherpesvirus Infection Is CD4 Independent In Vitro but CD4 Dependent In Vivo

Journal of Virology ◽

10.1128/jvi.73.2.1075-1079.1999 ◽

1999 ◽

Vol 73 (2) ◽

pp. 1075-1079 ◽

Cited By ~ 78

Author(s):

Philip G. Stevenson ◽

Peter C. Doherty

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Total Serum ◽

B Cell Activation ◽

Murine Gammaherpesvirus ◽

Vitro Effect

ABSTRACT The murine gammaherpesvirus MHV-68 multiplies in the respiratory epithelium after intranasal inoculation, then spreads to infect B cells in lymphoid germinal centers. Exposing B cells to MHV-68 in vitro caused an increase in cell size, up-regulation of the CD69 activation marker, and immunoglobulin M (IgM) production. The infectious process in vivo was also associated with increased CD69 expression on B cells in the draining lymph nodes and spleen, together with a rise in total serum Ig. However, whereas the in vitro effect on B cells was entirely T-cell independent, evidence of in vivo B-cell activation was minimal in CD4+ T-cell-deficient (I-Ab−/−) or CD4+ T-cell-depleted mice. Furthermore, the Ig present at high levels in serum was predominantly of the IgG class. Surprisingly, the titer of influenza virus-specific serum IgG in previously immunized mice fell following MHV-68 infection, suggesting that there was relatively little activation of memory B cells. Thus, CD4+T cells seemed both to amplify a direct viral activation of B cells in lymphoid tissue and to promote new Ig class switching despite a lack of obvious cognate antigen.

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