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.
Highlights
Notch expressed on CD4+ T cells transduces signals that mediate their effector functions and survival
Following the activation and proliferation of pathogen-specific CD4+ T cells, a fraction of the activated CD4+ T cells survive as long-lived memory CD4+ T cells that respond with enhanced kinetics and effector functions to subsequent infections[3,4]
Notch/Notch ligand interactions allow Notch receptors to be proteolytically cleaved in the extracellular domain by ADAM, which is followed by cleavage in the transmembrane domain by a γ-secretase complex
Summary
Notch expressed on CD4+ T cells transduces signals that mediate their effector functions and survival. Several reports have demonstrated that the intracellular domain of Notch ligands translocates into the nucleus and controls gene expression[20,21]. As those findings have not been repeated by in vivo studies, the physiological roles of signal transmission through Notch ligands remain unclear. The deletion of Dll[1] in CD4+ T cells attenuated the severity of experimental autoimmune encephalomyelitis (EAE) and was associated with impaired differentiation of Th1 and Th17 cells These data identify a novel mechanism for Dll1-mediated maintenance of activated/memory CD4+ T cells
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