Abnormal Th1 cell differentiation and IFN-gamma production in T lymphocytes from motheaten viable mice mutant for Src homology 2 domain-containing protein tyrosine phosphatase-1.
Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) plays an important role in T and B lymphocyte signaling; however, the function of SHP-1 in Th cell differentiation, in particular, the Th1 response, has not been defined. In this study, we provide evidence that SHP-1 phosphatase negatively regulates Th1 cell development and IFN-gamma production. Compared with the wild-type control, anti-CD3-activated mouse T lymphocytes carrying the motheaten viable mutation in the SHP-1 gene produced a significantly increased amount of IFN-gamma in the presence of IL-12. This increase was also seen at the basal level without IL-12 addition. Similarly, Th1 cell differentiation and proliferation of anti-CD3-activated SHP-1 mutant lymph node cells in the presence or absence of IL-12 were markedly enhanced, indicating a negative role for SHP-1 phosphatase in such lymphocyte activities. Interestingly, IL-12-induced activation of Jak2 and STAT4, critical components for IL-12-mediated cellular responses, was shortened or attenuated in mutant T cells. Together these results suggest that SHP-1 negatively regulates Th1 cell development and functions through a mechanism that is not directly related to IL-12 signaling.
Yu
Wen-Mei
WM
Department of Hematopoiesis, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, MD 20855, USA.
Wang
Siying
S
Keegan
Achsah D
AD
Williams
Mark S
MS
Qu
Cheng-Kui
CK
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000502:physiology; D018123:Receptors, Interleukin / Q000502:physiology; D053707:Receptors, Interleukin-12; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018909:src Homology Domains / Q000235:genetics*
D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse