Dataset Information

Staphylococcus aureus convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) T cells via the PD-1/PD-L1 axis.

ABSTRACT: The gut microbiota provides an important stimulus for the induction of regulatory T (Treg) cells in mice, whether this applies to newborn children is unknown. In Swedish children, Staphylococcus aureus has become a common early colonizer of the gut. Here, we sought to study the effects of bacterial stimulation on neonatal CD4(+) T cells for the induction of CD25(+) CD127(low) Treg cells in vitro. The proportion of circulating CD25(+) CD127(low) Treg cells and their expression of FOXP3, Helios and CTLA-4 was examined in newborns and adults. To evaluate if commensal gut bacteria could induce Treg cells, CellTrace violet-stained non-Treg cells from cord or peripheral blood from adults were co-cultured with autologous CD25(+) CD127(low) Treg cells and remaining mononuclear cells and stimulated with S. aureus. Newborns had a significantly lower proportion of CD25(+) CD127(low) Treg cells than adults, but these cells were Helios(+) and CTLA-4(+) to a higher extent than in adults. FOXP3(+) CD25(+) CD127(low) T cells were induced mainly in neonatal CellTrace-stained non-Treg cells after stimulation with S. aureus. In cell cultures from adults, S. aureus induced CD25(+) CD127(low) T cells only if sorted naive CD45RA(+) non-Treg cells were used, but these cells expressed less FOXP3 than those induced from newborns. Sorted neonatal CD25(+) CD127(low) T cells from S. aureus-stimulated cultures were still suppressive. Finally, blocking PD-L1 during stimulation reduced the induction of FOXP3(+) CD25(+) CD127(low) T cells. These results suggest that newborns have a higher proportion of circulating thymically derived Helios(+) Treg cells than adults and that S. aureus possess an ability to convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) Treg cells via the PD-1/PD-L1 axis.

SUBMITTER: Rabe H

PROVIDER: S-EPMC3930383 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Staphylococcus aureus convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) T cells via the PD-1/PD-L1 axis.

Rabe Hardis H Nordström Inger I Andersson Kerstin K Lundell Anna-Carin AC Rudin Anna A

Immunology 20140301 3

The gut microbiota provides an important stimulus for the induction of regulatory T (Treg) cells in mice, whether this applies to newborn children is unknown. In Swedish children, Staphylococcus aureus has become a common early colonizer of the gut. Here, we sought to study the effects of bacterial stimulation on neonatal CD4(+) T cells for the induction of CD25(+) CD127(low) Treg cells in vitro. The proportion of circulating CD25(+) CD127(low) Treg cells and their expression of FOXP3, Helios an ...[more]

PMID: 24708420

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Project description:Although immunoregulation of alloreactive human CTLs has been described, the direct influence of CD4(+) Tregs on CD8(+) cytotoxicity and the interactive mechanisms have not been well clarified. Therefore, human CD4(+)CD127(-)CD25(+)FOXP3(+) Tregs were generated in MLR, immunoselected and their allospecific regulatory functions and associated mechanisms were then tested using modified (51)Chromium release assays (Micro-CML), MLRs and CFSE-based multi-fluorochrome flow cytometry proliferation assays. It was observed that increased numbers of CD4(+)CD127(-)CD25(+)FOXP3(+) cells were generated after a 7 day MLR. After immunoselection for CD4(+)CD127(-)CD25(+) cells, they were designated as MLR-Tregs. When added as third component modulators, MLR-Tregs inhibited the alloreactive proliferation of autologous PBMC in a concentration dependent manner. The inhibition was quasi-antigen specific, in that the inhibition was non-specific at higher MLR-Treg modulator doses, but non-specificity disappeared with lower numbers at which specific inhibition was still significant. When tested in micro-CML assays CTL inhibition occurred with PBMC and purified CD8(+) responders. However, antigen specificity of CTL inhibition was observed only with unpurified PBMC responders and not with purified CD8(+) responders or even with CD8(+) responders plus Non-T "APC". However, allospecificity of CTL regulation was restored when autologous purified CD4(+) T cells were added to the CD8(+) responders. Proliferation of CD8(+) cells was suppressed by MLR-Tregs in the presence or absence of IL-2. Inhibition by MLR-Tregs was mediated through down-regulation of intracellular perforin, granzyme B and membrane-bound CD25 molecules on the responding CD8(+) cells. Therefore, it was concluded that human CD4(+)CD127(-)CD25(+)FOXP3(+) MLR-Tregs down-regulate alloreactive cytotoxic responses. Regulatory allospecificity, however, requires the presence of cognate responding CD4(+) T cells. CD8(+) CTL regulatory mechanisms include impaired proliferation, reduced expression of cytolytic molecules and CD25(+) activation epitopes.

Dataset Information

Staphylococcus aureus convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) T cells via the PD-1/PD-L1 axis.

Publications

Staphylococcus aureus convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) T cells via the PD-1/PD-L1 axis.

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