title: The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation.
abstract: The adaptor molecule signaling lymphocytic activation molecule-associated protein (SAP) plays critical roles during invariant natural killer T (iNKT) cell ontogeny. As a result, SAP-deficient humans and mice lack iNKT cells. The strict developmental requirement for SAP has made it difficult to discern its possible involvement in mature iNKT cell functions. By using temporal Cre recombinase-mediated gene deletion to ablate SAP expression after completion of iNKT cell development, we demonstrate that SAP is essential for T-cell receptor (TCR)-induced iNKT cell cytotoxicity against T-cell and B-cell leukemia targets in vitro and iNKT-cell-mediated control of T-cell leukemia growth in vivo. These findings are not restricted to the murine system: silencing RNA-mediated suppression of SAP expression in human iNKT cells also significantly impairs TCR-induced cytolysis. Mechanistic studies reveal that iNKT cell killing requires the tyrosine kinase Fyn, a known SAP-binding protein. Furthermore, SAP expression is required within iNKT cells to facilitate their interaction with T-cell targets and induce reorientation of the microtubule-organizing center to the immunologic synapse (IS). Collectively, these studies highlight a novel and essential role for SAP during iNKT cell cytotoxicity and formation of a functional IS.
authors: Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Rupali
authors: R
authors: Das
authors: Hamid
authors: H
authors: Bassiri
authors: Peng
authors: P
authors: Guan
authors: Susan
authors: S
authors: Wiener
authors: Pinaki P
authors: PP
authors: Banerjee
authors: Ming-Chao
authors: MC
authors: Zhong
authors: André
authors: A
authors: Veillette
authors: Jordan S
authors: JS
authors: Orange
authors: Kim E
authors: KE
authors: Nichols
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013569:Synapses / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; C114953:SH2D1A protein, human; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn