Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in T(H)2 cytokine regulation

Dominique Davidson; Xiaochu Shi; Shaohua Zhang; Hao Wang; Mona Nemer; Nobuyuki Ono; Shinji Ohno; Yusuke Yanagi; André Veillette

doi:10.1016/j.immuni.2004.10.005

Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in T(H)2 cytokine regulation

Immunity. 2004 Nov;21(5):707-17. doi: 10.1016/j.immuni.2004.10.005.

Authors

Dominique Davidson¹, Xiaochu Shi, Shaohua Zhang, Hao Wang, Mona Nemer, Nobuyuki Ono, Shinji Ohno, Yusuke Yanagi, André Veillette

Affiliation

¹ Laboratory of Molecular Oncology, Clinical Research Institute of Montreal, Montréal, Québec H2W 1R7, Canada.

PMID: 15539156
DOI: 10.1016/j.immuni.2004.10.005

Abstract

SAP is an adaptor mutated in X-linked lymphoproliferative disease. It plays a critical role in T helper 2 (T(H)2) cytokine production. This function was suggested to reflect the capacity of SAP to associate with SLAM family receptors and enable tyrosine phosphorylation signaling by these receptors through SAP-mediated recruitment of Src-related kinase FynT. Here, we addressed by genetic means the importance of the SAP-FynT interaction in normal T cell functions. By creating a mouse in which the FynT binding site of SAP was inactivated in the germ line (sap(R78A) mouse) and by analyzing mice lacking SAP, FynT or SLAM, evidence was obtained that the SAP-FynT cascade is indeed crucial for normal T(H)2 functions in vitro and in vivo. These data imply that SAP is necessary for T(H)2 cytokine regulation primarily as a result of its capacity to recruit FynT. They also establish a previously unappreciated role for FynT in SAP-dependent T(H)2 cytokine regulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD
Cytokines / biosynthesis*
DNA-Binding Proteins / genetics
GATA3 Transcription Factor
Glycoproteins / physiology
Immunoglobulin E / biosynthesis
Immunoglobulins / physiology
Intracellular Signaling Peptides and Proteins / physiology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Proto-Oncogene Proteins / physiology*
Proto-Oncogene Proteins c-fyn
Receptors, Antigen, T-Cell / physiology
Receptors, Cell Surface
Signaling Lymphocytic Activation Molecule Associated Protein
Signaling Lymphocytic Activation Molecule Family Member 1
Th2 Cells / immunology*
Trans-Activators / genetics

Substances

Antigens, CD
Cytokines
DNA-Binding Proteins
GATA3 Transcription Factor
Gata3 protein, mouse
Glycoproteins
Immunoglobulins
Intracellular Signaling Peptides and Proteins
Proto-Oncogene Proteins
Receptors, Antigen, T-Cell
Receptors, Cell Surface
Sh2d1a protein, mouse
Signaling Lymphocytic Activation Molecule Associated Protein
Trans-Activators
Signaling Lymphocytic Activation Molecule Family Member 1
Immunoglobulin E
Fyn protein, mouse
Proto-Oncogene Proteins c-fyn