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* Division of Pediatric Hematology-Oncology and Bone Marrow Transplantation,
Division of Pediatric Surgery,
Department of Anesthesiology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
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-
. Significantly, neutralizing Notch1R Ab inhibits NICD1 and HES-1 nuclear translocation, and production of IFN-. 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant K08AI51402 (to Y.M.V.), R01AR045593 (to J.P.), and from U.S. Immune Deficiency Network (to Y.M.V.).
2 Address correspondence and reprint requests to Dr. Yatin M. Vyas, Division of Pediatric Hematology-Oncology and Bone Marrow Transplantation, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. E-mail address: yatin.vyas{at}chp.edu
3 Abbreviations used in this paper: Dll, Delta-like ligand; NECD1, Notch extracellular domain 1; NICD1, Notch intracellular domain 1; NEXT, Notch extracellular truncation; DECD1, Dll1 extracellular domain; JECD1, Jagged1 extracellular domain; HES 1, hairy and enhancer of split 1; GLUT1, glucose transporter 1; IS, immunological synapse; SMAC, supramolecular activation clusters; SSC, signal sending cell; SRC, signal receiving cell; MTOC, microtubule organizing center; CTF, C-terminal fragment; NTF, N-terminal fragment.
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  N. Asano, T. Watanabe, A. Kitani, I. J. Fuss, and W. Strober Notch1 Signaling and Regulatory T Cell Function J. Immunol., March 1, 2008; 180(5): 2796 - 2804. [Abstract] [Full Text] [PDF]
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