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CD46-induced human Treg enhance B-cell responses.

ABSTRACT: Regulatory CD4(+) T cells (Treg) are important modulators of the immune response. Different types of Treg have been identified based on whether they are thymically derived (natural Treg) or induced in the periphery (adaptive Treg). We recently reported on an adaptive Treg phenotype that can be induced by the concomitant stimulation of human CD4(+) T cells through CD3 and the membrane complement regulator CD46. These complement (CD46)-induced regulatory T cells (cTreg) potently inhibit bystander T-cell proliferation through high-level secretion of IL-10. In addition, cTreg express granzyme B and exhibit cytotoxic effects toward activated effector T cells. Here, we analyzed the effect of cTreg on B-cell functions in a co-culture system. We found that cTreg enhance B-cell Ab production. This B-cell support is dependent on cell/cell contact as well as cTreg-derived IL-10. In addition, we show that T cells from a CD46-deficient patient are not capable of promoting B-cell responses, whereas CD46-deficient B cells have no intrinsic defect in Ig production. This finding may relate to a subset of CD46-deficient patients, who present with common variable immunodeficiency. Thus, the lack of cTreg function in optimizing B-cell responses could explain why some CD46-deficient patients develop common variable immunodeficiency.

SUBMITTER: Fuchs A

PROVIDER: S-EPMC2856319 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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CD46-induced human Treg enhance B-cell responses.

Fuchs Anja A Atkinson John P JP Fremeaux-Bacchi Veronique V Kemper Claudia C

European journal of immunology 20091101 11

Regulatory CD4(+) T cells (Treg) are important modulators of the immune response. Different types of Treg have been identified based on whether they are thymically derived (natural Treg) or induced in the periphery (adaptive Treg). We recently reported on an adaptive Treg phenotype that can be induced by the concomitant stimulation of human CD4(+) T cells through CD3 and the membrane complement regulator CD46. These complement (CD46)-induced regulatory T cells (cTreg) potently inhibit bystander ...[more]

PMID: 19784949

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Project description:Spontaneous term labour is associated with amplified inflammatory events in the myometrium including cytokine production and leukocyte infiltration; however, potential mechanisms regulating such events are not fully understood. We hypothesized that mechanical stretch of the uterine wall by the growing fetus facilitates peripheral leukocyte extravasation into the term myometrium through the release of various cytokines by uterine myocytes. Human myometrial cells (hTERT-HM) were subjected to static mechanical stretch; stretch-conditioned media was collected and analysed using 48-plex Luminex assay and ELISA. Effect of stretch-conditioned media on cell adhesion molecule expression of human uterine microvascular endothelial cells (UtMVEC-Myo) was detected by quantitative polymerase chain reaction (qPCR) and flow cytometry; functional assays testing leukocyte-endothelial interactions: adhesion of leukocytes to endothelial cells and transendothelial migration of calcein-labelled primary human neutrophils as well as migration of THP-1 monocytic cells were assessed by fluorometry. The current in vitro study demonstrated that mechanical stretch (i) directly induces secretion of multiple cytokines and chemokines by hTERT-HM cells (IL-6, CXCL8, CXCL1, migration inhibitory factor (MIF), VEGF, G-CSF, IL-12p70, bFGF and platelet-derived growth factor subunit B (PDGF-bb), P<0.05); stretch-induced cytokines (ii) enhance leukocyte adhesion to the endothelium of the surrounding uterine microvasculature by (iii) inducing the expression of endothelial cell adhesion molecules and (iv) directing the transendothelial migration of peripheral leukocytes. (vi) Chemokine-neutralizing antibodies and broad-spectrum chemokine inhibitor block leukocyte migration. Our data provide a proof of mechanical regulation for leukocyte recruitment from the uterine blood vessels to the myometrium, suggesting a putative mechanism for the leukocyte infiltrate into the uterus during labour and postpartum involution.

Dataset Information

CD46-induced human Treg enhance B-cell responses.

Publications

CD46-induced human Treg enhance B-cell responses.

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