Differential requirement for the SAP-Fyn interaction during NK T cell development and function

Selene Nunez-Cruz, W. C.Janice Yeo, Jennifer Rothman, Priti Ojha, Hamid Bassiri, Marisa Juntilla, Dominique Davidson, André Veillette, Gary A. Koretzky, Kim E. Nichols

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

The adaptor molecule SAP (signaling lymphocytic activation molecule-associated protein) plays a critical role during NK T (NKT) cell development in humans and mice. In CD4+ T cells, SAP interacts with the tyrosine kinase Fyn to deliver signals required for TCR-induced Th2-type cytokine production. To determine whether the SAP-dependent signals controlling NKT cell ontogeny rely on its binding to Fyn, we used the OP9-DL1 system to initiate structure function studies of SAP in murine NKT cell development. In cultures containing wild-type (WT) hematopoietic progenitors, we noted the transient emergence of cells that reacted with the NKT cell-specific agonist α-galactosyl ceramide and its analog PBS57. Sap-/- cells failed to give rise to NKT cells in vitro; however, their development could be rescued by re-expression of WT SAP. Emergence of NKT cells was also restored by a mutant version of SAP (SAP R78A) that cannot bind to Fyn, but with less efficiency than WT SAP. This finding was accentuated in vivo in Sap R78A knock-in mice as well as SapR78A competitive bone marrow chimeras, which retained NKT cells but at significantly reduced numbers compared with controls. Unlike SapR78A CD4+ T cells, which produce reduced levels of IL-4 following TCR ligation, α-galactosyl ceramide-stimulated NKT cells from the livers and spleens of SapR78A mice produced Th2 cytokines and activated NK cells in a manner mimicking WT cells. Thus, SAP appears to use differential signaling mechanisms in NKT cells, with optimal ontogeny requiring Fyn binding, while functional responses occur independently of this interaction.

Original languageEnglish (US)
Pages (from-to)2311-2320
Number of pages10
JournalJournal of Immunology
Volume181
Issue number4
DOIs
StatePublished - Aug 15 2008
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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