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Transmission of survival signals through Delta-like 1 on activated CD4⁺ T cells.

ABSTRACT: Notch expressed on CD4⁺ T cells transduces signals that mediate their effector functions and survival. Although Notch signaling is known to be cis-inhibited by Notch ligands expressed on the same cells, the role of Notch ligands on T cells remains unclear. In this report we demonstrate that the CD4⁺ T cell Notch ligand Dll1 transduces signals required for their survival. Co-transfer of CD4⁺ T cells from Dll1^-/- and control mice into recipient mice followed by immunization revealed a rapid decline of CD4⁺ T cells from Dll1^-/- mice compared with control cells. Dll1^-/- mice exhibited lower clinical scores of experimental autoimmune encephalitis than control mice. The expression of Notch target genes in CD4⁺ T cells from Dll1^-/- mice was not affected, suggesting that Dll1 deficiency in T cells does not affect cis Notch signaling. Overexpression of the intracellular domain of Dll1 in Dll1-deficient CD4⁺ T cells partially rescued impaired survival. Our data demonstrate that Dll1 is an independent regulator of Notch-signaling important for the survival of activated CD4⁺ T cells, and provide new insight into the physiological roles of Notch ligands as well as a regulatory mechanism important for maintaining adaptive immune responses.

SUBMITTER: Furukawa T

PROVIDER: S-EPMC5034251 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Transmission of survival signals through Delta-like 1 on activated CD4+ T cells.

Furukawa Takahiro T Ishifune Chieko C Tsukumo Shin-Ichi SI Hozumi Katsuto K Maekawa Yoichi Y Matsui Naoko N Kaji Ryuji R Yasutomo Koji K

Scientific reports 20160923

Notch expressed on CD4+ T cells transduces signals that mediate their effector functions and survival. Although Notch signaling is known to be cis-inhibited by Notch ligands expressed on the same cells, the role of Notch ligands on T cells remains unclear. In this report we demonstrate that the CD4+ T cell Notch ligand Dll1 transduces signals required for their survival. Co-transfer of CD4+ T cells from Dll1-/- and control mice into recipient mice foll ...[more]

PMID: 27659682

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Project description:BackgroundMicrovesicles are vesicles shed by plasma membranes following cell activation and apoptosis. The role of lymphocyte-derived microvesicles in endothelial function remains poorly understood.MethodsCD4+ T cells isolated from peripheral blood of healthy human donors were stimulated using anti-CD3/anti-CD28-coated beads. Proteomic profiling of microvesicles was performed using linear discriminant analysis (LDA) from activated T cells (MV.Act) and nonactivated T cells (MV.NAct). In addition, data processing analysis was performed using MaxQUANT workflow. Differentially expressed proteins found in MV.Act or MV.NAct samples with identification frequency = 100%, which were selected by both LDA (p < .01) and MaxQUANT (p < .01) workflows, were defined as "high-confidence" differentially expressed proteins. Functional effects of MV.Act on human primary microvascular endothelial cells were analysed.ResultsT cells released large amounts of microvesicles upon stimulation. Proteomic profiling of microvesicles using LDA identified 2279 proteins (n = 2110 and n = 851 proteins in MV.Act and MV.NAct, respectively). Protein-protein interaction network models reconstructed from both differentially expressed proteins (n = 594; LDA p ≤ .01) and "high-confidence" differentially expressed proteins (n = 98; p ≤ .01) revealed that MV.Act were enriched with proteins related to immune responses, protein translation, cytoskeleton organisation and TNFα-induced apoptosis. For instance, MV.Act were highly enriched with IFN-γ, a key proinflammatory pathway related to effector CD4+ T cells. Endothelial cell incubation with MV.Act induced superoxide generation, apoptosis, endothelial wound healing impairment and endothelial monolayer barrier disruption.ConclusionsT cell receptor-mediated activation of CD4+ T cells stimulates the release of microvesicles enriched with proteins involved in immune responses, inflammation and apoptosis. T cell-derived microvesicles alter microvascular endothelial function and barrier permeability, potentially promoting tissue inflammation.

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Transmission of survival signals through Delta-like 1 on activated CD4⁺ T cells.

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Transmission of survival signals through Delta-like 1 on activated CD4<sup>+</sup> T cells.

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