Journal article
Antiparallel segregation of notch components in the immunological synapse directs reciprocal signaling in allogeneic Th:DC conjugates
The Journal of immunology (1950), Vol.179(2), pp.819-829
07/15/2007
DOI: 10.4049/jimmunol.179.2.819
PMID: 17617572
Abstract
Direct T cell allorecognition underlies the development of a vigorous immune response in the clinical setting of acute graft rejection. The Notch pathway is an important regulator of Th immune responses, yet the molecular underpinnings of directional Notch signaling, otherwise critical for binary cell fate decisions, are unknown during autologous or allogeneic Th:DC interactions. Using the development of immune synapses (IS) in the allogeneic, human physiological Th:DC interaction, we demonstrate that Th-Notch1 receptor and DC-Notch ligands (Delta-like1, Jagged1) cluster in their apposed central-supramolecular-activation-clusters (cSMAC), whereas DC-Notch1 receptor and Th-Notch ligands cluster in their apposed peripheral-SMAC (pSMAC). Numb, a negative regulator of Notch, is excluded from the IS-microdomains where Notch1 receptor accumulates. This antiparallel arrangement across the partnering halves of the IS supports reciprocal Notch signal propagation in the DC-to-Th direction via the cSMAC and Th-to-DC direction via the pSMAC. As a result, processed Notch1 receptor (Notch-intracellular-domain, NICD1) and its ligands, as well as their downstream targets, HES-1 and phosphorylated-STAT3, accumulate in the nuclei of both cell-types. There is also enhancement of GLUT1 expression in both cell-types, as well as increased production of Th-IFN-gamma. Significantly, neutralizing Notch1R Ab inhibits NICD1 and HES-1 nuclear translocation, and production of IFN-gamma. In contrast, the IS formed during Ag-nonspecific, autologous Th:DC interaction is immature, resulting in failure of Notch1 receptor segregation and subsequent nuclear translocation of NICD1. Our results provide the first evidence for the asymmetric recruitment of Notch components in the Th:DC immunological synapse, which regulates the bidirectional Notch signal propagation.
Details
- Title: Subtitle
- Antiparallel segregation of notch components in the immunological synapse directs reciprocal signaling in allogeneic Th:DC conjugates
- Creators
- Winifred H Luty - Division of Pediatric Hematology-Oncology and Bone Marrow Transplantation, Children's Hospital of Pittsburgh, University of Pittsburgh, PA 15213, USADavid RodebergJerome ParnessYatin M Vyas
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.179(2), pp.819-829
- DOI
- 10.4049/jimmunol.179.2.819
- PMID
- 17617572
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- K08AI51402 / NIAID NIH HHS R01AR045593 / NIAMS NIH HHS K08 AI051402 / NIAID NIH HHS
- Language
- English
- Date published
- 07/15/2007
- Academic Unit
- Stead Family Department of Pediatrics
- Record Identifier
- 9984093596602771
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