title: Diacylglycerol kinase ζ limits the generation of natural regulatory T cells.
abstract: Natural regulatory T (nT(reg)) cells are important for maintaining tolerance to self- and foreign antigens, and they are thought to develop from thymocytes that receive strong T cell receptor (TCR)-mediated signals in the thymus. TCR engagement leads to the activation of phospholipase C-γ1, which generates the lipid second messenger diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate. We used mice that lack the ζ isoform of DAG kinase (DGKζ), which metabolizes DAG to terminate its signaling, to enhance TCR-mediated signaling and identify critical signaling events in nT(reg) cell development. Loss of DGKζ resulted in increased numbers of thymic CD25(+)Foxp3(-)CD4(+) nT(reg) cell precursors and Foxp3(+)CD4(+) nT(reg) cells in a cell-autonomous manner. DGKζ-deficient T cells exhibited increased nuclear translocation of the nuclear factor κB subunit c-Rel, as well as enhanced extracellular signal-regulated kinase (ERK) phosphorylation in response to TCR stimulation, suggesting that these downstream pathways may contribute to nT(reg) cell development. Indeed, reducing c-Rel abundance or blocking ERK phosphorylation abrogated the increased generation of nTreg cells by DGKζ-deficient thymocytes. The extent of ERK phosphorylation correlated with TCR-mediated acquisition of Foxp3 in immature thymocytes in vitro. Furthermore, the development of nT(reg) cells was augmented in mice in which ERK activation was selectively enhanced in T cells. Together, these data suggest that DGKζ regulates the development of nT(reg) cells by limiting the extent of activation of the ERK and c-Rel signaling pathways.
authors.affiliation: 1Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 10194, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Tao
authors.initials: T
authors.lastname: Zou
authors.forename: Rohan P
authors.initials: RP
authors.lastname: Joshi
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Leichner
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Pimentel
authors.forename: Connie L
authors.initials: CL
authors.lastname: Sommers
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D019852:Diacylglycerol Kinase / Q000172:deficiency* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; D048049:Extracellular Signal-Regulated MAP Kinases