The Sensing of Environmental Stimuli by Follicular Dendritic Cells Promotes Immunoglobulin A Generation in the Gut

Suzuki, Keiichiro; Maruya, Mikako; Kawamoto, Shimpei; Sitnik, Katarzyna; Kitamura, Hiroshi; Agace, William W.; Fagarasan, Sidonia

doi:10.1016/j.immuni.2010.07.003

Cited by 216 publications

(262 citation statements)

References 52 publications

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“…We and others previously reported that absence of vitamin A causes a se- vere reduction of IgA cells in the gut because of impaired germinal center formation in Peyer's patches, defective class switching of B2 cells from IgM to IgA, and impaired homing of IgA plasmablasts from the Peyer's patches to the gut lamina propria (15)(16)(17). However, many IgA plasma cells can be generated from the peritoneal B1 cells by germinal center-independent pathways (3,18).…”

Section: Resultsmentioning

confidence: 93%

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Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells

Maruya¹,

Suzuki²,

Fujimoto

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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B1 cells represent a distinct subset of B cells that produce most of the natural serum IgM and much of the gut IgA and function as an important component of early immune responses to pathogens. The development of B1 cells depends on the nuclear factor of activated T cells c1 (NFATc1), a transcription factor abundantly expressed by B1 cells but not by conventional B2 cells. However, the factors that regulate the expression of NFATc1 in B1 cells remain unknown. Here we show that a vitamin A-deficient diet results in reduction of NFATc1 expression in B1 cells and almost complete loss of the B1 cell compartment. As a consequence, vitamin A-deficient mice have reduced serum IgM and are unable to mount T cell-independent antibody responses against bacterial antigens. We demonstrate that injection of all-trans retinoic acid induces the expression of NFATc1, particularly from the constitutive P2 promoter, and leads to the increase of the B1 cells. Thus, the retinoic acid-dependent pathway is critical for regulating NFATc1 expression and for maintenance of the natural memory B cell compartment.innate-like B cells | self-replenishment | natural antibodies | peritoneal-associated adipose tissues | retinoids

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Section: Resultsmentioning

confidence: 93%

“…All mice were bred and maintained as previously described (15). VAD mice were prepared as described (17).…”

Section: Methodsmentioning

confidence: 99%

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Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells

Maruya¹,

Suzuki²,

Fujimoto

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…These cells have recently been isolated and studied in vitro (72,73). The implications of adjuvant binding to the FDC have previously not been analyzed (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…FDCs are known to express TLR4 and can be activated upon challenge with LPS, thus promoting accessory activity and enhancing IgG responses (74). Upon activation, FDC increase expression of adhesion molecules (VCAM-1, ICAM-1, and mucosal addressin cell adhesion molecule-1), CXCL13, BAFF, and cytokines (IL-1b, IL-5, IL-10 and IL-15) and upregulate TLR4 expression (26,72,73). Whether CTA1-DD activated FDC in a TLR-independent fashion and which promoting effects it had leading to upregulated GC reactions will be studied in detail in future experiments.…”

Section: Discussionmentioning

confidence: 99%

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

Mattsson

Stensson

Schön

et al. 2011

The Journal of Immunology

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A detailed understanding of how activation of innate immunity can be exploited to generate more effective vaccines is critically required. However, little is known about how to target adjuvants to generate safer and better vaccines. In this study, we describe an adjuvant that, through complement activation and binding to follicular dendritic cells (FDC), dramatically enhances germinal center (GC) formation, which results in greatly augmented Ab responses. The nontoxic CTA1-DD adjuvant hosts the ADP-ribosylating CTA1 subunit from cholera toxin and a dimer of the D fragment from Staphylococcus aureus protein A. We found that T cell-dependent, but not -independent, responses were augmented by CTA1-DD. GC reactions and serum Ab titers were both enhanced in a dose-dependent manner. This effect required complement activation, a property of the DD moiety. Deposition of CTA1-DD to the FDC network appeared to occur via the conduit system and was dependent on complement receptors on the FDC. Hence, Cr2−/− mice failed to augment GC reactions and exhibited dramatically reduced Ab responses, whereas Ribi adjuvant demonstrated unperturbed adjuvant function in these mice. Noteworthy, the adjuvant effect on priming of specific CD4 T cells was found to be intact in Cr2−/− mice, demonstrating that the CTA1-DD host both complement-dependent and -independent adjuvant properties. This is the first demonstration, to our knowledge, of an adjuvant that directly activates complement, enabling binding of the adjuvant to the FDC, which subsequently strongly promoted the GC reaction, leading to augmented serum Ab titers and long-term memory development.

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New helping friends for B cells

2012

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Over the past decade, a growing recognition of the importance of neutralizing antibodies in host defense combined with the success of B-cell depletion therapies in treating autoimmune disorders has led to an increased focus on better understanding the pathways underpinning B-cell antibody production. In general, B cells require cognate interaction with T helper cells in the germinal center of lymphoid follicles to generate protective antibodies. However, recent evidence shows that B cells receive additional help from invariant natural killer T cells, dendritic cells, and various granulocytes, including neutrophils, eosinophils, and basophils. These innate immune cells enhance T-cell-dependent antibody responses by delivering B-cell helper signals both in the germinal center and at postgerminal center lymphoid sites such as the bone marrow. In addition to enhancing and complementing the B-cell helper activity of canonical T cells, invariant natural killer T cells, dendritic cells, and granulocytes can deliver T cell-independent B-cell helper signals at the mucosal interface and in the marginal zone of the spleen to initiate rapid innate-like antibody responses. Here, we discuss recent advances in the role of adaptive and innate B-cell helper signals in antibody diversification and production.

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The Sensing of Environmental Stimuli by Follicular Dendritic Cells Promotes Immunoglobulin A Generation in the Gut

Cited by 216 publications

References 52 publications

Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells

Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

New helping friends for B cells

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