Synergistic control of T cell development and tumor suppression by diacylglycerol kinase alpha and zeta.
Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that convert DAG to phosphatidic acid (PA), the physiologic functions of which have been poorly defined. We report here that DGK alpha and zeta synergistically promote T cell maturation in the thymus. Absence of both DGKalpha and zeta (DGKalpha(-/-)zeta(-/-)) results in a severe decrease in the number of CD4(+)CD8(-) and CD4(-)CD8(+) single-positive thymocytes correlating with increased DAG-mediated signaling. Positive selection, but not negative selection, is impaired in DGKalpha(-/-)zeta(-/-) mice. The developmental blockage in DGKalpha(-/-)zeta(-/-) mice can be partially overcome by treatment with PA. Furthermore, decreased DGK activity also promotes thymic lymphomagenesis accompanying elevated Ras and Erk1/2 activation. Our data demonstrate a synergistic and critical role of DGK isoforms in T cell development and tumor suppression, and indicate that DGKs not only terminate DAG signaling but also initiate PA signaling in thymocytes to promote positive selection.
Guo
Rishu
R
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Wan
Chi-Keung
CK
Carpenter
Jeffery H
JH
Mousallem
Talal
T
Boustany
Rose-Mary N
RM
Kuan
Chien-Tsun
CT
Burks
A Wesley
AW
Zhong
Xiao-Ping
XP
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019852:Diacylglycerol Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D008223:Lymphoma / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D013950:Thymus Gland / Q000201:enzymology; D046509:Tissue Culture Techniques; D018631:ras Proteins / Q000378:metabolism
D007527:Isoenzymes; D019852:Diacylglycerol Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins