The src homology 2 domain-containing tyrosine phosphatase 2 regulates primary T-dependent immune responses and Th cell differentiation.
The src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) plays an important role in development and in growth factor receptor signaling pathways, yet little is known of its role in the immune system. We generated mice expressing a dominant-negative version of the protein, SHP2(CS), specifically in T cells. In SHP2(CS) mice, T cell development appears normal with regard to both negative and positive selection. However, SHP2(CS) T cells express higher levels of activation markers, and aged mice have elevated serum Abs. This is associated with a marked increase in IL-4, IL-5, and IL-10 secretion by SHP2(CS) T cells in vitro. In addition, primary thymus-dependent B cell responses are deficient in SHP2(CS) mice. We show that whereas TCR-induced linker for activation of T cells phosphorylation is defective, CTLA-4 and programmed death-1 signaling are not affected by SHP2(CS) expression. Our results suggest that a key action of wild-type SHP2 is to suppress differentiation of T cells to the Th2 phenotype.
Salmond
Robert J
RJ
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham, Cambridge, United Kingdom. robert.salmond@bbsrc.ac.uk
Huyer
Gregory
G
Kotsoni
Anastasia
A
Clements
Lisa
L
Alexander
Denis R
DR
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008211:Lymphocyte Cooperation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D015848:Interleukin-5; D047908:Intracellular Signaling Peptides and Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D004247:DNA; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse