Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand

Grewal, Iqbal S.; Xu, Jinbao; Flavell, Richard A.

doi:10.1038/378617a0

Cited by 445 publications

(299 citation statements)

References 15 publications

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“…Yellin et al, 1994;Van Kooten and Banchereau, 1996 . In what ways may local interactions between CD40L on activated T cells and CD40 on macrophages contribute to disease? First, signals through CD40 are involved in T cell Ž priming Van Essen et al, 1995;Grewal et al, 1995; . In agreement with this, it was shown recently that production of Ž .…”

Section: Accessory Molecules: Cd40-cd40lmentioning

confidence: 99%

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Laman

Meurs²,

Schellekens³

et al. 1998

Journal of Neuroimmunology

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Ž .Accessory molecules and cytokines are involved in the immunopathogenesis of multiple sclerosis MS and experimental autoimmune Ž . encephalomyelitis EAE in rodent models, and are potential targets for immunotherapy. Evaluation of such experimental therapies requires appropriate animal models. Therefore, we analysed the expression of selected accessory molecules and cytokines in the brain of Ž . marmoset monkeys Callithrix jacchus with acute EAE, a newly described non-human primate model for MS. All animals experienced active disease clinically and histopathologically with strong resemblance to MS. Perivascular infiltrates of mononuclear cells showed abundant expression of CD40. CD40 was expressed on macrophages, indicating that T cell priming and macrophage effector functions Ž . Ž . may result from local CD40-CD40L interactions. CD40 ligand CD40L and B7-2 CD86 were also expressed, but to a lower extent, Ž . while B7-1 CD80 expression was limited. Both pro-inflammatory and anti-inflammatory cytokines were produced within individual Ž . lesions during active disease IFN-a, IFN-g , TNF-a, IL-1a , IL-1b, IL-2, IL-4, IL-10 and IL-12 . This suggests that relative levels rather than sequential expression of Th1-and Th2-type cytokines determine disease activity. These findings demonstrate the value of EAE in marmoset monkeys as a model to assess the role of accessory molecules and cytokines in multiple sclerosis, and to evaluate targeted intervention. q

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Section: Accessory Molecules: Cd40-cd40lmentioning

confidence: 99%

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Laman

Meurs²,

Schellekens³

et al. 1998

Journal of Neuroimmunology

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“…CD40 belongs to the super-family of TNF receptors, and expression of CD40 is detected during early B cell ontogeny [27][28][29][30]. In mature B cells, signaling through CD40 promotes survival, somatic hyper-mutation and class-switch recombination, and the defective CD40 signaling results in hyper-IgM syndrome [31,32].…”

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confidence: 99%

Potential role of CARMA1 in CD40‐induced splenic B cell proliferation and marginal zone B cell maturation

Pappu¹,

Lin²

2006

Eur J Immunol

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NF‐κB activation through B cell receptor (BCR) ligation is critical for B cell development, survival and antigen‐mediated activation of B cells. CARD domain and MAGUK‐domain containing protein‐1 (CARMA1), recently identified adaptor molecule, has been shown to play an essential role in BCR‐induced NF‐κB activation. CARMA1‐deficient B cells fail to proliferate upon BCR stimulation, leading to defective humoral responses. Surprisingly, CARMA1‐deficient B cells are also defective in CD40‐induced proliferation. The mechanisms responsible for CD40‐induced proliferation defect have not yet been characterized. In this study, we show that signaling cascades activated by CD40 stimulation are largely unaffected in CARMA1‐deficient B cells. Instead, we have found that the defective proliferation of CARMA1‐deficient B cells is due to two events. First, CARMA1‐deficient B cells show defective cell‐cycle progression. Secondly, the numbers of marginal zone (MZ) B cells, which are the main responders upon CD40 stimulation, are greatly diminished in CARMA1‐deficient mice. Since B cell maturation requires basal signaling through BCR and NF‐κB activation, we propose that impaired BCR signaling in CARMA1‐deficient mice leads to defective maturation of MZ B cell population, which in turn, contributes to impaired proliferation upon CD40 stimulation.

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“…A number of in vitro and in vivo studies have implicated direct signaling of B cells by CD40 as a critical step at numerous stages of the B cell response including proliferation and clonal expansion, Ig production, germinal center formation, isotype switching, affinity maturation, and induction of B cell memory (12)(13)(14)(15)(16)(17). Experiments in animals deficient in CD40L or CD40 suggest that these molecules also play a primary role in CD4 ϩ T cell activation (18,19). Although CD40 appears to deliver an important proliferation/differentiation signal to B cells, CD40 signal transduction also induces up-regulation of CD80/CD86 which provides costimulatory signals to the responding T cells.…”

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confidence: 99%

Th2-Dependent B Cell Responses in the Absence of CD40-CD40 Ligand Interactions

Chirmule

Tazelaar

Wilson

2000

The Journal of Immunology

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CD40 is thought to play a central role in T cell-dependent humoral responses through two distinct mechanisms. CD4+ T helper cells are activated via CD40-dependent Ag presentation in which CD80/CD86 provides costimulation through CD28. In addition, engagement of CD40 on B cells provides a direct pathway for activation of humoral responses. We used a model of adenovirus-mediated gene transfer of β-galactosidase (lacZ) into murine lung to evaluate the specific CD40-dependent pathways required for humoral immunity at mucosal surfaces of the lung. Animals deficient in CD40L failed to develop T and B cell responses to vector. Activation of Th2 cells, which normally requires CD40-dependent stimulation of APCs, was selectively reconstituted in CD40 ligand-deficient mice by systemic administration of an Ab that is agonistic to CD28. Surprisingly, this resulted in the development of a functional humoral response to vector as evidenced by formation of germinal centers and production of antiadenovirus IgG1 and IgA that neutralized and prevented effective readministration of vector. The CD28-dependent B cell response required CD4+ T cells and was mediated via IL-4. These studies indicate that CD40 signals to the B cells are not necessary for CD4+ Th2 cell-dependent humoral responses to be generated.

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Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand

Cited by 445 publications

References 15 publications

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Potential role of CARMA1 in CD40‐induced splenic B cell proliferation and marginal zone B cell maturation

Th2-Dependent B Cell Responses in the Absence of CD40-CD40 Ligand Interactions

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