Dataset Information

CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells.

ABSTRACT: IL-17-producing CD4(+) T cells have been recognized as key players in organ-related autoimmune disease; however, the parameters that govern their development are yet to be elucidated fully. By using both in vivo and in vitro systems, we have investigated the role of antigen dose, pathogen-associated molecular patterns, and CD40-CD40 ligand (CD40L) cross-talk in Th17 differentiation. We found that the strength of antigenic stimulation critically influenced the extent of Th17 differentiation, because high, but not low or intermediate, antigen concentrations led to IL-17 production. Strong antigenic stimulation of T cells up-regulated CD40L expression, which in concert with certain microbial stimuli (i.e., cytosine phosphate guanine, curdlan, and zymosan) synergistically increased dendritic cell (DC) IL-6 production and Th17 polarization. CD40-deficient DCs exhibited reduced cytokine release and failed to drive Th17 development in vitro. These results were confirmed in vivo where the absence of CD40-CD40L cross-talk was found to prevent the expansion of IL-17-producing cells and accordingly the development of experimental autoimmune encephalitis. Our data demonstrate that CD40-CD40L cross-talk is important for Th17 development by translating strong T cell receptor and microbial stimuli into IL-6 production.

SUBMITTER: Iezzi G

PROVIDER: S-EPMC2630101 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells.

Iezzi Giandomenica G Sonderegger Ivo I Ampenberger Franziska F Schmitz Nicole N Marsland Benjamin J BJ Kopf Manfred M

Proceedings of the National Academy of Sciences of the United States of America 20090109 3

IL-17-producing CD4(+) T cells have been recognized as key players in organ-related autoimmune disease; however, the parameters that govern their development are yet to be elucidated fully. By using both in vivo and in vitro systems, we have investigated the role of antigen dose, pathogen-associated molecular patterns, and CD40-CD40 ligand (CD40L) cross-talk in Th17 differentiation. We found that the strength of antigenic stimulation critically influenced the extent of Th17 differentiation, beca ...[more]

PMID: 19136631

Similar Datasets

Project description:BackgroundAstrocytes, which play an active role in chronic inflammatory diseases like multiple sclerosis, exist close to mast cells with which they share perivascular localization. We previously demonstrated the possibility that astrocytes and mast cells interact in vitro and in vivo. This study aimed to investigate the signaling pathways and the role for astrocytes in the interaction of astrocytes and mast cells.MethodsWe co-cultured human U87 glioblastoma (U87) and human mast cell-1 (HMC-1) cell lines, and mouse cerebral cortices-derived astrocytes and mouse bone marrow-derived mast cells (BMMCs). Intracellular Ca2+ ([Ca2+]i) was measured by confocal microscopy; CD40 siRNA by Silencer Express Kit; small GTPases by GTP-pull down assay; PKCs, MAPKs, CD40, CD40L, Jak1/2, STAT1, TNF receptor 1 (TNFR1) by Western blot; NF-κB and AP-1 by EMSA; cytokines by RT-PCR. An experimental allergic encephalomyelitis (EAE) model was induced using myelin oligodendrocyte glycoprotein (MOG) peptide and pertussis toxin in mice. Co-localization of TNFR1 and astrocytes in EAE brain tissues was determined by immunohistochemistry.ResultsEach astrocyte co-culture had increases in [Ca2+]i levels, release of cytokines and chemokines; activities of Rho-family GTPases, NF-κB/AP-1/STAT1727, and Jack1/2, STAT1701. These effects were inhibited by anti-CD40 antibody or CD40 siRNA, and signaling pathways for Jak1/2 were inhibited by anti-TNFR1 antibody. EAE score, expression of TNFR1, and co-localization of TNFR1 and astrocytes were enhanced in brain of the EAE model. Anti-CD40 antibody or 8-oxo-dG pretreatment reduced these effects in EAE model.ConclusionsThese data suggest that astrocytes activated by the CD40-CD40L interaction in co-culture induce inflammatory cytokine production via small GTPases, and the secreted cytokines re-activate astrocytes via Jak/STAT1701 pathways, and then release more cytokines that contribute to exacerbating the development of EAE. These findings imply that the pro-inflammatory mediators produced by cell-to-cell cross-talk via interaction of CD40-CD40L may be as a promising therapeutic target for neurodegenerative diseases like MS.

Project description:The CD40 receptor and its ligand CD40L is one of the most critical molecular pairs of the stimulatory immune checkpoints. Both CD40 and CD40L have a membrane form and a soluble form generated by proteolytic cleavage or alternative splicing. CD40 and CD40L are widely expressed in various types of cells, among which B cells and myeloid cells constitutively express high levels of CD40, and T cells and platelets express high levels of CD40L upon activation. CD40L self-assembles into functional trimers which induce CD40 trimerization and downstream signaling. The canonical CD40/CD40L signaling is mediated by recruitment of TRAFs and NF-κB activation, which is supplemented by signal pathways such as PI3K/AKT, MAPKs and JAK3/STATs. CD40/CD40L immune checkpoint leads to activation of both innate and adaptive immune cells via two-way signaling. CD40/CD40L interaction also participates in regulating thrombosis, tissue inflammation, hematopoiesis and tumor cell fate. Because of its essential role in immune activation, CD40/CD40L interaction has been regarded as an attractive immunotherapy target. In recent years, significant advance has been made in CD40/CD40L-targeted therapy. Various types of agents, including agonistic/antagonistic monoclonal antibodies, cellular vaccines, adenoviral vectors and protein antagonist, have been developed and evaluated in early-stage clinical trials for treating malignancies, autoimmune diseases and allograft rejection. In general, these agents have demonstrated favorable safety and some of them show promising clinical efficacy. The mechanisms of benefits include immune cell activation and tumor cell lysis/apoptosis in malignancies, or immune cell inactivation in autoimmune diseases and allograft rejection. This review provides a comprehensive overview of the structure, processing, cellular expression pattern, signaling and effector function of CD40/CD40L checkpoint molecules. In addition, we summarize the progress, targeted diseases and outcomes of current ongoing and completed clinical trials of CD40/CD40L-targeted therapy.

Dataset Information

CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells.

Publications

CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets