CD4+ T Lymphocytes Expressing CD40 Ligand Help the IgM Antibody Response to Soluble Pneumococcal Polysaccharides via an Intermediate Cell Type

Jeurissen, A; Billiau, An; Moens, Leen; Li, Shengqiao; Landuyt, Willy; Wuyts, Greet; Boon, Louis; Waer, Mark; Ceuppens, Jan L.; Bossuyt, Xavier

doi:10.4049/jimmunol.176.1.529

Cited by 16 publications

(11 citation statements)

References 27 publications

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“…Within the hematopoietic compartment, CD40 may signal in dendritic cells (DCs), macrophages, or, possibly, other B cells to lead to the production of factors that augment autoreactive B cell survival. Non-cell-autonomous effects of CD40 signaling have previously been suggested to influence the survival of plasma cells and to contribute to anti-pneumococcal polysaccharide antibody responses (22,23). Although they show the existence of an extrinsic pathway, our present studies do not exclude the possibility that the CD40L-CD40 pathway can also act in a cell-intrinsic manner to promote autoantigen-binding B cell survival.…”

Section: Discussioncontrasting

confidence: 76%

Naive CD4 T cells constitutively express CD40L and augment autoreactive B cell survival

Lesley

Kelly

et al. 2006

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

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Chronic engagement of the B cell receptor by soluble autoantigen leads to reduced B cell survival. Using the Ig and hen egg lysozyme double transgenic mouse model, we demonstrate that the survival of soluble autoantigen-engaged B cells is further reduced in mice lacking CD4 T cells or deficient in CD40. Mixed bone marrow chimera experiments reveal that, under homeostatic conditions, the CD40L-CD40 pathway can augment autoreactive B cell survival in a non-cell-autonomous manner. Naive CD4 T cells are shown to constitutively express CD40L mRNA and protein, although cell surface CD40L abundance is low because of engagement with CD40 on other cells. These observations indicate that the CD40L-CD40 pathway can augment the survival of autoantigen-engaged B cells in the absence of T cell activation. We propose that constitutive CD40L expression by naive CD4 T cells influences the composition of the B cell repertoire and may also affect the homeostasis of other cell types such as regulatory T cells in lymphoid organs.homeostasis A utoreactive B cells that arise in the bone marrow are kept in check by a series of self-tolerance mechanisms. Cells with B cell receptors (BCRs) that bind multivalent autoantigens in the bone marrow undergo receptor editing or deletion. B cells that are specific for autoantigens of lower valency are able to enter the periphery, but chronic exposure to autoantigen induces IgM downmodulation and reduced coupling of the BCR to downstream pathways, a state known as B cell anergy (1). A study in humans has shown that many autoreactive B cells reach the periphery but fail to enter the long-lived mature B cell pool (2).In the Ig͞hen egg lysozyme (HEL) double transgenic (Tg) mouse model, the HEL autoantigen-binding B cells have a short (Ϸ1 week) half-life compared with the 4-week half-life of Ig Tg B cells in the absence of HEL (3, 4). The basis for this difference in lifespan is not fully defined, but anergic B cells were shown to have elevated expression of the proapoptotic molecule BIM and were more dependent on the prosurvival factor BAFF (5, 6). A further reduction in autoantigen-binding B cell survival was observed when the Ig͞HEL transgenes were crossed onto a recombinase-activating gene 1 (RAG1)-deficient background (7). RAG1-deficient mice were not found to have reduced BAFF production (5), leaving the basis for this effect unclear.Here we establish that naive CD4 T cells augment HEL autoantigen-binding B cell survival. Examination of CD40 as a candidate receptor downstream of CD4 T cells revealed that autoantigenbinding B cells have reduced survival in the absence of CD40 expression by hematopoietic cells. Mixed bone marrow chimera analysis revealed that the CD40L-CD40 pathway can rescue autoantigen-binding B cells through a non-cell-autonomous mechanism. Moreover, we show that CD40L is constitutively expressed by naive CD4 T cells and that surface levels are down-modulated by interactions with CD40-expressing cells. These findings indicate that, in addition to the well established role of th...

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Section: Discussioncontrasting

confidence: 76%

Naive CD4 T cells constitutively express CD40L and augment autoreactive B cell survival

Lesley

Kelly

et al. 2006

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

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“…Given that IgM is the most primitive Ab among the five isotypes (IgM, IgA, IgE, IgD and IgG) known in mammals, which was initially developed in fish and conserved throughout evolution (43), it is reasonable to suggest that CD154 and CD40 participation in IgM production may be the role they initially played in adaptive humoral immunity. This function was conserved from fish to mammals, because CD154 and CD40 also participate in the production of IgM in mammals (44). However, functional diversification of these molecules may have accompanied the precise evolution of immunity in higher vertebrates, because the most important function of CD154 and CD40 in higher vertebrates changed from primary immune response (IgM production) to secondary immune response when Ab class switching happened from IgM to IgA, IgG, or IgE.…”

Section: Discussionmentioning

confidence: 99%

CD154-CD40 Interactions Are Essential for Thymus-Dependent Antibody Production in Zebrafish: Insights into the Origin of Costimulatory Pathway in Helper T Cell-Regulated Adaptive Immunity in Early Vertebrates

Gong

Xiang²,

Shao³

2009

The Journal of Immunology

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The CD154-CD40-mediated costimulatory pathway is critical for T-B cell cooperation in thymus-dependent (TD) immune response in mammals. However, little is known about its existence and occurrence in lower vertebrates. Here, we report on the identification and functional characterization of CD154 and CD40 homologs from the zebrafish (Danio rerio) model. Zebrafish CD154 is a type II membrane-bound protein with a TNF homology domain in its extracellular C-terminal region, whose tertiary structure is a sandwich containing two stacked sheets with “jelly roll” topology, just as the human TNF members do. The zebrafish CD40 is a type I membrane-bound protein with a sequence pattern of four cysteine-rich domains in its extracellular N-terminal region. The consensus TNFR-associated factor (TRAF)2- and TRAF6-binding motifs in mammalian CD40 are found in the cytoplasmic tail of zebrafish CD40, which indicates similar signal transduction mechanisms to higher vertebrates. Zebrafish CD154 and CD40 are widely distributed and can be up-regulated by thymus-dependent Ag. The production of IgM was dramatically decreased by anti-CD154 or soluble CD40, and it was enhanced by soluble CD154 or CD154-encoding plasmid in vivo. Thymus-dependent Ag-induced CD154 expression was inhibited by cyclosporin A, suggesting that CD154 functionally associates with T cells. Double immunofluorescence staining showed that CD40 and membrane IgM colocalized in B cells. CD154-CD40 binding assays showed that CD154 specifically binds to CD40 at homodimeric form. Our results provide the first evidence for the existence of the functional CD154-CD40-mediated costimulatory pathway and helper T cell regulatory mechanism underlying adaptive immunity in a fish species.

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“…4 The reported incidence of anaphylactic-like reactions has ranged from 0.03% to 1.10% of patients and has been attributed to the active ingredient and not to contaminants. 3,7 With regard to vaccines, hypersensitivity reaction to BCG vaccine containing high-molecular-weight (100 kd) dextran has been described in a newborn subject and explained by the binding of passively transferred maternal dextran-reactive IgG. 5 Increased IgG levels to dextran have been demonstrated in patients with hypersensitivity reactions; an IgE-mediated mechanism has been also postulated but ruled out by most of the studies.…”

Section: Dextran-specific Igg Response In Hypersensitivity Reactions mentioning

confidence: 99%

“…3 In the present study we evaluated the regulation of the human antibody response to S pneumoniae. 7 We hypothesize that the CD40-CD40L interaction between CD14 1 mononuclear cells and CD4 1 T cells could induce the release of soluble factors that can further stimulate B lymphocytes to produce IgM and IgG anti-caps-PS antibodies. Consistent with studies in mice, 5 we found that the IgG polysaccharide-specific and protein-specific response to S pneumoniae was dependent on CD4 1 T lymphocytes and the CD40-CD40L interaction.…”

mentioning

confidence: 97%

The human polysaccharide- and protein-specific immune response to Streptococcus pneumoniae is dependent on CD4+ T lymphocytes, CD14+ monocytes, and the CD40–CD40 ligand interaction

Moens

Wuyts

Boon³

et al. 2008

Journal of Allergy and Clinical Immunology

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Conti A, et al. Molecular characterization and allergenic activity of Lyc e 2 (beta-fructofuranosidase), a glycosylated allergen of tomato. Eur J Biochem 2003;270:1327-37. 5. Lorenz Y, Enrique E, Lequynh L, Fotisch K, Retzek M, Biemelt S, et al. Skin prick tests reveal stable and heritable reduction of allergenic potency of gene-silenced tomato fruits.The human polysaccharide-and protein-specific immune response to Streptococcus pneumoniae is dependent on CD4 1 T lymphocytes, CD14 1 monocytes, and the CD40-CD40 ligand interactionTo the Editor: Streptococcus pneumoniae is a major cause of pneumonia, septicemia, and meningitis. It causes great morbidity and mortality throughout the world. In particular, young children, the elderly, and immunocompromised individuals are susceptible to pneumococcal infections. Host protection against pneumococcal infections is mediated by antibodies against pneumococcal surface proteins and capsular polysaccharides (caps-PSs). 1 Caps-PSs are a main determinant of virulence of S pneumoniae, and antibodies to caps-PSs are protective against infection with S pneumoniae. Some pneumococcal surface proteins, such as pneumococcal surface protein A (PspA), are also considered virulence factors.Whereas proteins are T lymphocyte-dependent antigens, caps-PSs are considered T lymphocyte-independent type 2 (TI-2) antigens. Although T lymphocytes are not needed for induction of the antibody response to TI-2 antigens, they are involved in the regulation of this antibody response. 2 The role of T lymphocytes in the regulation of the antibody production to TI-2 antigens is poorly understood. Little is known regarding the mechanisms by which intact S pneumoniae elicits protein-and caps-PS-specific antibodies in human subjects. In the present study we immunized humanized mice with severe combined immunodeficiency (SCID) with heat-inactivated S pneumoniae as a model to study the human antibody response to S pneumoniae.To evaluate the role of CD4 1 T cells in the antibody response to pneumococcal caps-PSs and PspA, 6-to 8-week-old SCID mice were treated with TMb1 (an anti-murine IL-2 receptor b-chain antibody used to deplete murine natural killer cells and to improve transplant survival 3 ) and transplanted (in peritoneum) either with PBMCs (containing 4 3 10 6 B lymphocytes, n 5 6) or with PBMCs depleted of CD4 1 cells (by using microbeads; Miltenyi Biotec, Bergisch Gladbach, Germany; n 5 6). After transplantation, the mice were immunized with heat-inactivated S pneumoniae serotype 3 (2 3 10 8 colony-forming units). Two weeks after immunization, antibodies were measured by means of ELISA (with preabsorption of the sera with caps-PS serotype 22F [5 mg/L] for anti-caps-PS). 4,5 SCID/SCID mice reconstituted with PBMCs, but not with PBMCs depleted of CD4 1 cells, produced high levels of IgM and IgG antibodies against caps-PSs and PspA (data not shown; P < .03, Mann-Whitney U test).

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CD4+ T Lymphocytes Expressing CD40 Ligand Help the IgM Antibody Response to Soluble Pneumococcal Polysaccharides via an Intermediate Cell Type

Cited by 16 publications

References 27 publications

Naive CD4 T cells constitutively express CD40L and augment autoreactive B cell survival

Naive CD4 T cells constitutively express CD40L and augment autoreactive B cell survival

CD154-CD40 Interactions Are Essential for Thymus-Dependent Antibody Production in Zebrafish: Insights into the Origin of Costimulatory Pathway in Helper T Cell-Regulated Adaptive Immunity in Early Vertebrates

The human polysaccharide- and protein-specific immune response to Streptococcus pneumoniae is dependent on CD4+ T lymphocytes, CD14+ monocytes, and the CD40–CD40 ligand interaction

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