Regulation of lipid signaling by diacylglycerol kinases during T cell development and function

Frontiers in Immunology

Volumn 4, Issue JUL, 2013, Pages

  Krishna, Sruti ^a   Zhong, Xiao Ping ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Diacylglycerol kinase; Macrophages; Mast cells; Phosphatidic acid; T cell activation; T cell development; T cell receptor; T cell tolerance

Indexed keywords

CALCINEURIN; CD28 ANTIGEN; CHIMERIN; DIACYLGLYCEROL; DIACYLGLYCEROL KINASE; DIACYLGLYCEROL KINASE INHIBITOR; GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 2; LIPID; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MITOGEN ACTIVATED PROTEIN KINASE 3; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; PHOSPHATIDIC ACID; PHOSPHATIDYLINOSITOL 4 PHOSPHATE KINASE; PHOSPHOLIPASE D; PHOSPHOPROTEIN PHOSPHATASE 1; PROTEIN BCL 10; PROTEIN KINASE C; PROTEIN KINASE D; PROTEIN SH2; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE PHOSPHATASE SHP 1; RAF PROTEIN; RAS PROTEIN; SIGNALING LYMPHOCYTE ACTIVATION MOLECULE ASSOCIATED PROTEIN; T LYMPHOCYTE RECEPTOR; TRIPHOSPHOINOSITIDE; UNINDEXED DRUG;

ANTINEOPLASTIC ACTIVITY; CD8+ T LYMPHOCYTE; CELL ACTIVATION; CELL FUNCTION; CELL LINEAGE; CELL MATURATION; CELL MEMBRANE; CELLULAR IMMUNITY; CELLULAR SECRETION; CLONAL ANERGY; CYTOTOXIC T LYMPHOCYTE; ENZYME ACTIVITY; HUMAN; IMMUNOLOGICAL TOLERANCE; LEUKEMIA CELL LINE; MACROPHAGE; METABOLIC REGULATION; MICROTUBULE ORGANIZING CENTER; NATURAL KILLER T CELL; NONHUMAN; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; THYMOCYTE; VIRUS INFECTION;

EID: 84883700624     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2013.00178     Document Type: Review

References (159)

1. Eyster KM. The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist. Adv Physiol Educ (2007) 31:5-16. doi:10.1152/advan.00088.2006
2. Fernandis AZ, Wenk MR. Membrane lipids as signaling molecules. Curr Opin Lipidol (2007) 18:121-8. doi:10.1097/MOL.0b013e328082e4d5
3. Merida I, Avila-Flores A, Merino E. Diacylglycerol kinases: at the hub of cell signalling. Biochem J (2008) 409:1-18. doi:10.1042/BJ20071040
4. Cai J, Abramovici H, Gee SH, Topham MK. Diacylglycerol kinases as sources of phosphatidic acid. Biochim Biophys Acta (2009) 1791:942-8. doi:10.1016/j.bbalip.2009.02.010
5. Sakane F, Imai S, Kai M, Yasuda S, Kanoh H. Diacylglycerol kinases: why so many of them? Biochim Biophys Acta (2007) 1771:793-806. doi:10.1016/j.bbalip.2007.04.006
6. Zhong XP, Hainey EA, Olenchock BA, Zhao H, Topham MK, Koretzky GA. Regulation of T cell receptor-induced activation of the Ras-ERK pathway by diacylglycerol kinase zeta. J Biol Chem , 2002. 277, 31089-98. doi:10.1074/jbc.M203818200
7. Zhong XP, Guo R, Zhou H, Liu C, Wan CK. Diacylglycerol kinases in immune cell function and self-tolerance. Immunol Rev (2008) 224:249-64. doi:10.1111/j.1600-065X.2008.00647.x
8. Breitkreutz D, Braiman-Wiksman L, Daum N, Denning MF, Tennenbaum T. Protein kinase C family: on the crossroads of cell signaling in skin and tumor epithelium. J Cancer Res Clin Oncol (2007) 133:793-808. doi:10.1007/s00432-007-0280-3
9. Gould CM, Newton AC. The life and death of protein kinase C. Curr Drug Targets (2008) 9:614-25. doi:10.2174/138945008785132411
10. Huang J, Lo PF, Zal T, Gascoigne NR, Smith BA, Levin SD, et al. CD28 plays a critical role in the segregation of PKC theta within the immunologic synapse. Proc Natl Acad Sci U S A (2002) 99:9369-73. doi:10.1073/pnas.142298399
11. Yokosuka T, Kobayashi W, Sakata-Sogawa K, Takamatsu M, Hashimoto-Tane A, Dustin ML, et al. Spatiotemporal regulation of T cell costimulation by TCRCD28 microclusters and protein kinase C theta translocation. Immunity (2008) 29:589-601. doi:10.1016/j.immuni.2008.08.011
12. Sun Z, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ, Gandhi L, et al. PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes. Nature (2000) 404:402-7. doi:10.1038/35006090
13. Isakov N, Altman A. Protein kinase C(theta) in T cell activation. Annu Rev Immunol (2002) 20:761-94. doi:10.1146/annurev.immunol.20.100301.064807
14. Hayashi K, Altman A. Protein kinase C theta (PKCtheta): a key player in T cell life and death. Pharmacol Res (2007) 55:537-44. doi:10.1016/j.phrs.2007.04.009
15. Schmidt-Supprian M, Tian J, Grant EP, Pasparakis M, Maehr R, Ovaa H, et al. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-kappaB activation. Proc Natl Acad Sci U S A (2004) 101:4566-71. doi:10.1073/pnas.0400885101
16. Fang X, Wang R, Ma J, Ding Y, Shang W, Sun Z. Ameliorated ConA-induced hepatitis in the absence of PKC-theta. PLoS ONE (2012) 7:e31174. doi:10.1371/journal.pone.0031174
17. Manicassamy S, Gupta S, Huang Z, Sun Z. Protein kinase C-theta-mediated signals enhance CD4+ T cell survival by up-regulating Bcl-xL. J Immunol (2006) 176:6709-16.
18. Werlen G, Jacinto E, Xia Y, Karin M. Calcineurin preferentially synergizes with PKC-theta to activate JNK and IL-2 promoter in T lymphocytes. EMBO J (1998) 17:3101-11. doi:10.1093/emboj/17.11.3101
19. Cannons JL, Yu LJ, Hill B, Mijares LA, Dombroski D, Nichols KE, et al. SAP regulates T(H)2 differentiation and PKC-theta-mediated activation of NF-kappaB1. Immunity (2004) 21:693-706. doi:10.1016/j.immuni.2004.09.012
20. Marsland BJ, Soos TJ, Spath G, Littman DR, Kopf M. Protein kinase C theta is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses. J Exp Med (2004) 200:181-9. doi:10.1084/jem.20032229
21. Kwon MJ, Ma J, Ding Y, Wang R, Sun Z. Protein kinase C-theta promotes Th17 differentiation via upregulation of Stat3. J Immunol (2012) 188:5887-97. doi:10.4049/jimmunol.1102941
22. Carrasco S, Merida I. Diacylglycerol-dependent binding recruits PKCtheta and RasGRP1 C1 domains to specific subcellular localizations in living T lymphocytes. Mol Biol Cell (2004) 15:2932-42. doi:10.1091/mbc.E03-11-0844
23. Roose JP, Mollenauer M, Gupta VA, Stone J, Weiss A. A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells. Mol Cell Biol (2005) 25:4426-41. doi:10.1128/MCB.25.11.4426-4441.2005
24. Ebinu JO, Stang SL, Teixeira C, Bottorff DA, Hooton J, Blumberg PM, et al. RasGRP links T-cell receptor signaling to Ras. Blood (2000) 95:3199-203.
25. Dower NA, Stang SL, Bottorff DA, Ebinu JO, Dickie P, Ostergaard HL, et al. RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nat Immunol (2000) 1:317-21. doi:10.1038/80799
26. Priatel JJ, Teh SJ, Dower NA, Stone JC, Teh HS. RasGRP1 transduces low-grade TCR signals which are critical for T cell development, homeostasis, and differentiation. Immunity (2002) 17:617-27. doi:10.1016/S1074-7613(02)00451-X
27. Chen Y, Ci X, Gorentla B, Sullivan SA, Stone JC, Zhang W, et al. Differential requirement of RasGRP1 for gammadelta T cell development and activation. J Immunol (2012) 189:61-71. doi:10.4049/jimmunol.1103272
28. Priatel JJ, Chen X, Huang YH, Chow MT, Zenewicz LA, Coughlin JJ, et al. RasGRP1 regulates antigen-induced developmental programming by naive CD8 T cells. J Immunol (2010) 184:666-76. doi:10.4049/jimmunol.0803521
29. Wang QJ. PKD at the crossroads of DAG and PKC signaling. Trends Pharmacol Sci (2006) 27:317-23. doi:10.1016/j.tips.2006.04.003
30. Rozengurt E, Rey O, Waldron RT. Protein kinase D signaling. J Biol Chem (2005) 280:13205-8. doi:10.1074/jbc.R500002200
31. Marklund U, Lightfoot K, Cantrell D. Intracellular location and cell context-dependent function of protein kinase D. Immunity (2003) 19:491-501. doi:10.1016/S1074-7613(03)00260-7
32. Mullin MJ, Lightfoot K, Marklund U, Cantrell DA. Differential requirement for RhoA GTPase depending on the cellular localization of protein kinase D. J Biol Chem (2006) 281:25089-96. doi:10.1074/jbc.M603591200
33. Brose N, Rosenmund C. Move over protein kinase C, you've got company: alternative cellular effectors of diacylglycerol and phorbol esters. J Cell Sci (2002) 115:4399-411. doi:10.1242/jcs.00122
34. Koch H, Hofmann K, Brose N. Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform. Biochem J (2000) 349:247-53. doi:10.1042/0264-6021:3490247
35. Shirakawa R, Higashi T, Tabuchi A, Yoshioka A, Nishioka H, Fukuda M, et al. Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets. J Biol Chem (2004) 279:10730-7. doi:10.1074/jbc.M309426200
36. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell (2003) 115:461-73. doi:10.1016/S0092-8674(03)00855-9
37. Menager MM, Menasche G, Romao M, Knapnougel P, Ho CH, Garfa M, et al. Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nat Immunol (2007) 8:257-67. doi:10.1038/ni1431
38. Johnson JL, Hong H, Monfregola J, Kiosses WB, Catz SD. Munc13-4 restricts motility of Rab27a-expressing vesicles to facilitate lipopolysaccharide-induced priming of exocytosis in neutrophils. J Biol Chem (2011) 286:5647-56. doi:10.1074/jbc.M110.184762
39. Monfregola J, Johnson JL, Meijler MM, Napolitano G, Catz SD. MUNC13-4 protein regulates the oxidative response and is essential for phagosomal maturation and bacterial killing in neutrophils. J Biol Chem (2012) 287:44603-18. doi:10.1074/jbc.M112.414029
40. Song Y, Ailenberg M, Silverman M. Human munc13 is a diacylglycerol receptor that induces apoptosis and may contribute to renal cell injury in hyperglycemia. Mol Biol Cell (1999) 10:1609-19.
41. Caloca MJ, Garcia-Bermejo ML, Blumberg PM, Lewin NE, Kremmer E, Mischak H, et al. Beta2-chimaerin is a novel target for diacylglycerol: binding properties and changes in subcellular localization mediated by ligand binding to its C1 domain. Proc Natl Acad Sci U S A (1999) 96:11854-9. doi:10.1073/pnas.96.21.11854
42. Yang C, Kazanietz MG. Chimaerins: GAPs that bridge diacylglycerol signalling and the small G-protein Rac. Biochem J (2007) 403:1-12. doi:10.1042/BJ20061750
43. Caloca MJ, Delgado P, Alarcon B, Bustelo XR. Role of chimaerins, a group of Rac-specific GTPase activating proteins, in T-cell receptor signaling. Cell Signal (2008) 20:758-70. doi:10.1016/j.cellsig.2007.12.015
44. Siliceo M, Garcia-Bernal D, Carrasco S, Diaz-Flores E, Coluccio Leskow F, Teixido J, et al. Beta2-chimaerin provides a diacylglycerol-dependent mechanism for regulation of adhesion and chemotaxis of T cells. J Cell Sci (2006) 119:141-52. doi:10.1242/jcs.02722
45. Jenkins GM, Frohman MA. Phospholipase D: a lipid centric review. Cell Mol Life Sci (2005) 62:2305-16. doi:10.1007/s00018-005-5195-z
46. Csaki LS, Reue K. Lipins: multifunctional lipid metabolism proteins. Annu Rev Nutr (2010) 30:257-72. doi:10.1146/annurev.nutr.012809.104729
47. Wang X, Devaiah SP, Zhang W, Welti R. Signaling functions of phosphatidic acid. Prog Lipid Res (2006) 45:250-78. doi:10.1016/j.plipres.2006.01.005
48. Foster DA. Regulation of mTOR by phosphatidic acid?. Cancer Res (2007) 67:1-4. doi:10.1158/0008-5472.CAN-06-3016
49. Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science (2001) 294:1942-5. doi:10.1126/science.1066015
50. Chen J, Fang Y. A novel pathway regulating the mammalian target of rapamycin (mTOR) signaling. Biochem Pharmacol (2002) 64:1071-7. doi:10.1016/S0006 -2952(02)01263-7
51. Yoon MS, Sun Y, Arauz E, Jiang Y, Chen J. Phosphatidic acid activates mammalian target of rapamycin complex 1 (mTORC1) kinase by displacing FK506 binding protein 38 (FKBP38) and exerting an allosteric effect. J Biol Chem (2011) 286:29568-74. doi:10.1074/jbc.M111.262816
52. Winter JN, Fox TE, Kester M, Jefferson LS, Kimball SR. Phosphatidic acid mediates activation of mTORC1 through the ERK signaling pathway. Am J Physiol Cell Physiol (2010) 299:C335-44. doi:10.1152/ajpcell.00039.2010
53. Toschi A, Lee E, Xu L, Garcia A, Gadir N, Foster DA. Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin. Mol Cell Biol (2009) 29:1411-20. doi:10.1128/MCB.00782-08
54. Avila-Flores A, Santos T, Rincon E, Merida I. Modulation of the mammalian target of rapamycin pathway by diacylglycerol kinase-produced phosphatidic acid. J Biol Chem (2005) 280:10091-9. doi:10.1074/jbc.M412296200
55. Lim HK, Choi YA, Park W, Lee T, Ryu SH, Kim SY, et al. Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway. J Biol Chem (2003) 278:45117-27. doi:10.1074/jbc.M303789200
56. Andresen BT, Rizzo MA, Shome K, Romero G. The role of phosphatidic acid in the regulation of the Ras/MEK/Erk signaling cascade. FEBS Lett (2002) 531:65- 8. doi:10.1016/S0014-5793(02)03483-X
57. Ghosh S, Strum JC, Sciorra VA, Daniel L, Bell RM. Raf-1 kinase possesses distinct binding domains for phosphatidylserine and phosphatidic acid. Phosphatidic acid regulates the translocation of Raf-1 in 12-O-tetradecanoylphorbol-13-acetate-stimulated Madin-Darby canine kidney cells. J Biol Chem (1996) 271:8472- 80. doi:10.1074/jbc.271.14.8472
58. Rizzo MA, Shome K, Vasudevan C, Stolz DB, Sung TC, Frohman MA, et al. Phospholipase D and its product, phosphatidic acid, mediate agonist-dependent raf-1 translocation to the plasma membrane and the activation of the mitogen-activated protein kinase pathway. J Biol Chem (1999) 274:1131-9. doi:10.1074/jbc.274.2.1131
59. Shome K, Vasudevan C, Romero G. ARF proteins mediate insulin-dependent activation of phospholipase D. Curr Biol (1997) 7:387-96. doi:10.1016/S0960- 9822(06)00186-2
60. Rizzo MA, Shome K, Watkins SC, Romero G. The recruitment of Raf-1 to membranes is mediated by direct interaction with phosphatidic acid and is independent of association with Ras. J Biol Chem (2000) 275:23911-8. doi:10.1074/jbc.M001553200
61. Morrison DK. KSR: a MAPK scaffold of the Ras pathway?. J Cell Sci (2001) 114:1609-12.
62. Kraft CA, Garrido JL, Fluharty E, Leiva-Vega L, Romero G. Role of phosphatidic acid in the coupling of the ERK cascade. J Biol Chem (2008) 283:36636-45. doi:10.1074/jbc.M804633200
63. Zhao C, Du G, Skowronek K, Frohman MA, Bar-Sagi D. Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nat Cell Biol (2007) 9:706-12. doi:10.1038/ncb1594
64. Mor A, Campi G, Du G, Zheng Y, Foster DA, Dustin ML, et al. The lymphocyte function-associated antigen-1 receptor costimulates plasma membrane Ras via phospholipase D2. Nat Cell Biol (2007) 9:713-9. doi:10.1038/ncb1592
65. Norambuena A, Metz C, Vicuna L, Silva A, Pardo E, Oyanadel C, et al. Galectin-8 induces apoptosis in Jurkat T cells by phosphatidic acid-mediated ERK1/2 activation supported by protein kinase A down-regulation. J Biol Chem (2009) 284:12670-9. doi:10.1074/jbc.M808949200
66. Tribulatti MV, Cattaneo V, Hellman U, Mucci J, Campetella O. Galectin-8 provides costimulatory and proliferative signals to T lymphocytes. J Leukoc Biol (2009) 86:371-80. doi:10.1189/jlb.0908529
67. Cockcroft S. Phosphatidic acid regulation of phosphatidylinositol 4-phosphate 5-kinases. Biochim Biophys Acta (2009) 1791:905-12. doi:10.1016/j.bbalip.2009.03.007
68. Moritz A, de Graan PN, Gispen WH, Wirtz KW. Phosphatidic acid is a specific activator of phosphatidylinositol-4-phosphate kinase. J Biol Chem (1992) 267:7207-10.
69. Jenkins GH, Fisette PL, Anderson RA. Type I phosphatidylinositol 4-phosphate 5-kinase isoforms are specifically stimulated by phosphatidic acid. J Biol Chem (1994) 269:11547-54.
70. Jarquin-Pardo M, Fitzpatrick A, Galiano FJ, First EA, Davis JN. Phosphatidic acid regulates the affinity of the murine phosphatidylinositol 4-phosphate 5- kinase-Ibeta for phosphatidylinositol-4-phosphate. J Cell Biochem (2007) 100:112-28. doi:10.1002/jcb.21027
71. Luo B, Prescott SM, Topham MK. Diacylglycerol kinase zeta regulates phosphatidylinositol 4-phosphate 5-kinase Ialpha by a novel mechanism. Cell Signal (2004) 16:891-7. doi:10.1016/j.cellsig.2004.01.010
72. Galandrini R, Micucci F, Tassi I, Cifone MG, Cinque B, Piccoli M, et al. Arf6: a new player in FcgammaRIIIA lymphocyte-mediated cytotoxicity. Blood (2005) 106:577-83. doi:10.1182/blood-2004-10-4100
73. Micucci F, Capuano C, Marchetti E, Piccoli M, Frati L, Santoni A, et al. PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway. Blood (2008) 111:4165-72. doi:10.1182/blood-2007-08-108886
74. Cohen PT. Protein phosphatase 1 - targeted in many directions. J Cell Sci (2002) 115:241-56.
75. Jones JA, Hannun YA. Tight binding inhibition of protein phosphatase-1 by phosphatidic acid. Specificity of inhibition by the phospholipid. J Biol Chem (2002) 277:15530-8. doi:10.1074/jbc.M111555200
76. Jones JA, Rawles R, Hannun YA. Identification of a novel phosphatidic acid binding domain in protein phosphatase-1. Biochemistry (2005) 44:13235-45. doi:10.1021/bi0505159
77. Li X, Schwacha MG, Chaudry IH, Choudhry MA. A role of PP1/PP2A in mesenteric lymph node T cell suppression in a two-hit rodent model of alcohol intoxication and injury. J Leukoc Biol (2006) 79:453-62. doi:10.1189/jlb.0705369
78. Lorenz U. SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol Rev (2009) 228:342-59. doi:10.1111/j.1600-065X.2008.00760.x
79. Shultz LD, Schweitzer PA, Rajan TV, Yi T, Ihle JN, Matthews RJ, et al. Mutations at the murine motheaten locus are within the hematopoietic cell proteintyrosine phosphatase (Hcph) gene. Cell (1993) 73:1445-54. doi:10.1016/0092-8674(93)90369-2
80. Zhang J, Somani AK, Yuen D, Yang Y, Love PE, Siminovitch KA. Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection. J Immunol (1999) 163:3012-21.
81. Fowler CC, Pao LI, Blattman JN, Greenberg PD. SHP-1 in T cells limits the production of CD8 effector cells without impacting the formation of long-lived central memory cells. J Immunol (2010) 185:3256-67. doi:10.4049/jimmunol.1001362
82. Tomic S, Greiser U, Lammers R, Kharitonenkov A, Imyanitov E, Ullrich A, et al. Association of SH2 domain protein tyrosine phosphatases with the epidermal growth factor receptor in human tumor cells. Phosphatidic acid activates receptor dephosphorylation by PTP1C. J Biol Chem (1995) 270:21277-84. doi:10.1074/jbc.270.36.21277
83. Frank C, Keilhack H, Opitz F, Zschornig O, Bohmer FD. Binding of phosphatidic acid to the protein-tyrosine phosphatase SHP-1 as a basis for activity modulation. Biochemistry (1999) 38:11993-2002. doi:10.1021/bi982586w
84. Takahama Y. Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol (2006) 6:127-35. doi:10.1038/nri1781
85. Weerkamp F, Pike-Overzet K, Staal FJ. T-sing progenitors to commit. Trends Immunol (2006) 27:125-31. doi:10.1016/j.it.2006.01.006
86. Ellmeier W, Sawada S, Littman DR. The regulation of CD4 and CD8 coreceptor gene expression during T cell development. Annu Rev Immunol (1999) 17:523- 54. doi:10.1146/annurev.immunol.17.1.523
87. Taniuchi I, Ellmeier W. Transcriptional and epigenetic regulation of CD4/CD8 lineage choice. Adv Immunol (2011) 110:71-110. doi:10.1016/B978-0-12-387663 -8.00003-X
88. Misslitz A, Bernhardt G, Forster R. Trafficking on serpentines: molecular insight on how maturating T cells find their winding paths in the thymus. Immunol Rev (2006) 209:115-28. doi:10.1111/j.0105-2896.2006.00351.x
89. Bunting MD, Comerford I, McColl SR. Finding their niche: chemokines directing cell migration in the thymus. Immunol Cell Biol (2011) 89:185-96. doi:10.1038/icb.2010.142
90. Jameson SC, Hogquist KA, Bevan MJ. Positive selection of thymocytes. Annu Rev Immunol (1995) 13:93-126. doi:10.1146/annurev.iy.13.040195.000521
91. Dervovic D, Zuniga-Pflucker JC. Positive selection of T cells, an in vitro view. Semin Immunol (2010) 22:276-86. doi:10.1016/j.smim.2010.04.014
92. Sprent J, Kishimoto H. The thymus and negative selection. Immunol Rev (2002) 185:126-35. doi:10.1034/j.1600-065X.2002.18512.x
93. Von Boehmer H, Melchers F. Checkpoints in lymphocyte development and autoimmune disease. Nat Immunol (2010) 11:14-20. doi:10.1038/ni.1794
94. Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol (2003) 21:139-76. doi:10.1146/annurev.immunol.21.120601.141107
95. Wiegers GJ, Kaufmann M, Tischner D, Villunger A. Shaping the T-cell repertoire: a matter of life and death. Immunol Cell Biol (2011) 89:33-9. doi:10.1038/icb.2010.127
96. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature (2004) 427:355-60. doi:10.1038/nature02284
97. Cyster JG, Schwab SR. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol (2012) 30:69-94. doi:10.1146/annurevimmunol- 020711-075011
98. Michie AM, Trop S, Wiest DL, Zuniga-Pflucker JC. Extracellular signal-regulated kinase (ERK) activation by the pre-T cell receptor in developing thymocytes in vivo. J Exp Med (1999) 190:1647-56. doi:10.1084/jem.190.11.1647
99. Golec DP, Dower NA, Stone JC, Baldwin TA. RasGRP1, but not RasGRP3, is required for efficient thymic beta-selection and ERK activation downstream of CXCR4. PLoS ONE (2013) 8:e53300. doi:10.1371/journal.pone.0053300
100. Fu G, Chen Y, Yu M, Podd A, Schuman J, He Y, et al. Phospholipase C{gamma}1 is essential for T cell development activation, and tolerance. J Exp Med (2010) 207:309-18. doi:10.1084/jem.20090880
101. Swan KA, Alberola-Ila J, Gross JA, Appleby MW, Forbush KA, Thomas JF, et al. Involvement of p21ras distinguishes positive and negative selection in thymocytes. EMBO J (1995) 14:276-85.
102. Alberola-Ila J, Forbush KA, Seger R, Krebs EG, Perlmutter RM. Selective requirement for MAP kinase activation in thymocyte differentiation. Nature (1995) 373:620-3. doi:10.1038/373620a0
103. Pages G, Guerin S, Grall D, Bonino F, Smith A, Anjuere F, et al. Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science (1999) 286:1374-7. doi:10.1126/science.286.5443.1374
104. Fischer AM, Katayama CD, Pages G, Pouyssegur J, Hedrick SM. The role of erk1 and erk2 in multiple stages of T cell development. Immunity (2005) 23:431- 43. doi:10.1016/j.immuni.2005.08.013
105. Mahalingam M, Cooper JA. Phosphorylation of mammalian eIF4E by Mnk1 and Mnk2: tantalizing prospects for a role in translation. Prog Mol Subcell Biol (2001) 27:132-42. doi:10.1007/978-3-662-09889-9_5
106. Buxade M, Parra-Palau JL, Proud CG. The Mnks: MAP kinase-interacting kinases (MAP kinase signal-integrating kinases). Front Biosci (2008) 13:5359-73. doi:10.2741/3086
107. Gorentla BK, Krishna S, Shin J, Inoue M, Shinohara ML, Grayson JM, et al. Mnk1 and 2 are dispensable for T cell development and activation but important for the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol (2013) 190:1026-37. doi:10.4049/jimmunol.1200026
108. Morley SC, Weber KS, Kao H, Allen PM. Protein kinase C-theta is required for efficient positive selection. J Immunol (2008) 181:4696-708.
109. Gruber T, Pfeifhofer-Obermair C, Baier G. PKCtheta is necessary for efficient activation of NFkappaB NFAT, and AP-1 during positive selection of thymocytes. Immunol Lett (2010) 132:6-11. doi:10.1016/j.imlet.2010.04.008
110. Schmidt-Supprian M, Courtois G, Tian J, Coyle AJ, Israel A, Rajewsky K, et al. Mature T cells depend on signaling through the IKK complex. Immunity (2003) 19:377-89. doi:10.1016/S1074-7613(03)00237-1
111. Jimi E, Strickland I, Voll RE, Long M, Ghosh S. Differential role of the transcription factor NF-kappaB in selection and survival of CD4+ and CD8+ thymocytes. Immunity (2008) 29:523-37. doi:10.1016/j.immuni
112. Guo R, Wan CK, Carpenter JH, Mousallem T, Boustany RM, Kuan CT, et al. Synergistic control of T cell development and tumor suppression by diacylglycerol kinase alpha and zeta. Proc Natl Acad Sci U S A (2008) 105:11909-14. doi:10.1073/pnas.0711856105
113. Gorentla BK, Wan CK, Zhong XP. Negative regulation of mTOR activation by diacylglycerol kinases. Blood (2011) 117:4022-31. doi:10.1182/blood-2010-08- 300731
114. Matsuda JL, Mallevaey T, Scott-Browne J, Gapin L. CD1d-restricted iNKT cells, the "Swiss-Army knife" of the immune system. Curr Opin Immunol (2008) 20:358-68. doi:10.1016/j.coi.2008.03.018
115. Elewaut D, Shaikh RB, Hammond KJ, De Winter H, Leishman AJ, Sidobre S, et al. NIK-dependent RelB activation defines a unique signaling pathway for the development of V alpha 14i NKT cells. J Exp Med (2003) 197:1623-33. doi:10.1084/jem.20030141
116. Sivakumar V, Hammond KJ, Howells N, Pfeffer K, Weih F. Differential requirement for Rel/nuclear factor kappa B family members in natural killer T cell development. J Exp Med (2003) 197:1613-21. doi:10.1084/jem.20022234
117. Stanic AK, Bezbradica JS, Park JJ, Van Kaer L, Boothby MR, Joyce S. Cutting edge: the ontogeny and function of Va14Ja18 natural T lymphocytes require signal processing by protein kinase C theta and NF-kappa B. J Immunol (2004) 172:4667-71.
118. Shen S, Chen Y, Gorentla BK, Lu J, Stone JC, Zhong XP. Critical roles of RasGRP1 for invariant NKT cell development. J Immunol (2011) 187:4467-73. doi:10.4049/jimmunol.1003798
119. Hu T, Gimferrer I, Simmons A, Wiest D, Alberola-Ila J. The Ras/MAPK pathway is required for generation of iNKT cells. PLoS ONE (2011) 6:e19890. doi:10.1371/journal.pone.0019890
120. Shen S, Wu J, Srivatsan S, Gorentla BK, Shin J, Xu L, et al. Tight regulation of diacylglycerol-mediated signaling is critical for proper invariant NKT cell development. J Immunol (2011) 187:2122-9. doi:10.4049/jimmunol.1100495
121. Zhong XP, Hainey EA, Olenchock BA, Jordan MS, Maltzman JS, Nichols KE, et al. Enhanced T cell responses due to diacylglycerol kinase zeta deficiency. Nat Immunol (2003) 4:882-90. doi:10.1038/ni958
122. Olenchock BA, Guo R, Carpenter JH, Jordan M, Topham MK, Koretzky GA, et al. Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol (2006) 7:1174-81. doi:10.1038/ni1400
123. Metzger TC, Anderson MS. Control of central and peripheral tolerance by Aire. Immunol Rev (2011) 241:89-103. doi:10.1111/j.1600-065X.2011.01008.x
124. Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol (2012) 4:4. doi:10.1101/cshperspect.a006957
125. Schwartz RH. T cell anergy. Annu Rev Immunol (2003) 21:305-34. doi:10.1146/annurev.immunol.21.120601.141110
126. Powell JD. The induction and maintenance of T cell anergy. Clin Immunol (2006) 120:239-46. doi:10.1016/j.clim.2006.02.004
127. Fathman CG, Lineberry NB. Molecular mechanisms of CD4+ T-cell anergy. Nat Rev Immunol (2007) 7:599-609. doi:10.1038/nri2131
128. Chappert P, Schwartz RH. Induction of T cell anergy: integration of environmental cues and infectious tolerance. Curr Opin Immunol (2010) 22:552-9. doi:10.1016/j.coi.2010.08.005
129. Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A. Transcriptional mechanisms underlying lymphocyte tolerance. Cell (2002) 109:719-31. doi:10.1016/S0092-8674(02)00767-5
130. Zha Y, Marks R, Ho AW, Peterson AC, Janardhan S, Brown I, et al. T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha. Nat Immunol (2006) 7:1166-73. doi:10.1038/ni1206-1343a
131. Sanjuan MA, Jones DR, Izquierdo M, Merida I. Role of diacylglycerol kinase alpha in the attenuation of receptor signaling. J Cell Biol (2001) 153:207-20. doi:10.1083/jcb.153.1.207
132. Merino E, Avila-Flores A, Shirai Y, Moraga I, Saito N, Merida I. Lck-dependent tyrosine phosphorylation of diacylglycerol kinase alpha regulates its membrane association in T cells. J Immunol (2008) 180:5805-15.
133. Matsubara T, Ikeda M, Kiso Y, Sakuma M, Yoshino K, Sakane F, et al. c-Abl tyrosine kinase regulates serum-induced nuclear export of diacylglycerol kinase alpha by phosphorylation at Tyr-218. J Biol Chem (2012) 287:5507-17. doi:10.1074/jbc.M111.296897
134. Baldanzi G, Pighini A, Bettio V, Rainero E, Traini S, Chianale F, et al. SAP-mediated inhibition of diacylglycerol kinase alpha regulates TCR-induced diacylglycerol signaling. J Immunol (2011) 187:5941-51. doi:10.4049/jimmunol.1002476
135. Santos T, Carrasco S, Jones DR, Merida I, Eguinoa A. Dynamics of diacylglycerol kinase zeta translocation in living T-cells. Study of the structural domain requirements for translocation and activity. J Biol Chem (2002) 277:30300-9. doi:10.1074/jbc.M200999200
136. Topham MK, Bunting M, Zimmerman GA, McIntyre TM, Blackshear PJ, Prescott SM. Protein kinase C regulates the nuclear localization of diacylglycerol kinase -zeta. Nature (1998) 394:697-700. doi:10.1038/29337
137. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, et al. The immunological synapse: a molecular machine controlling T cell activation. Science (1999) 285:221-7. doi:10.1126/science.285.5425.221
138. Dustin ML. T-cell activation through immunological synapses and kinapses. Immunol Rev (2008) 221:77-89. doi:10.1111/j.1600-065X.2008.00589.x
139. Topham MK, Prescott SM. Diacylglycerol kinase zeta regulates Ras activation by a novel mechanism. J Cell Biol (2001) 152:1135-43. doi:10.1083/jcb.152.6.1135
140. Gharbi SI, Rincon E, Avila-Flores A, Torres-Ayuso P, Almena M, Cobos MA, et al. Diacylglycerol kinase zeta controls diacylglycerol metabolism at the immunological synapse. Mol Biol Cell (2011) 22:4406-14. doi:10.1091/mbc.E11-03-0247
141. Geiger B, Rosen D, Berke G. Spatial relationships of microtubule-organizing centers and the contact area of cytotoxic T lymphocytes and target cells. J Cell Biol (1982) 95:137-43. doi:10.1083/jcb.95.1.137
142. Kupfer A, Dennert G, Singer SJ. Polarization of the Golgi apparatus and the microtubule-organizing center within cloned natural killer cells bound to their targets. Proc Natl Acad Sci U S A (1983) 80:7224-8. doi:10.1073/pnas.80.23.7224
143. Martin-Cofreces NB, Robles-Valero J, Cabrero JR, Mittelbrunn M, Gordon-Alonso M, Sung CH, et al. MTOC translocation modulates IS formation and controls sustained T cell signaling. J Cell Biol (2008) 182:951-62. doi:10.1083/jcb.200801014
144. Quann EJ, Merino E, Furuta T, Huse M. Localized diacylglycerol drives the polarization of the microtubule-organizing center in T cells. Nat Immunol (2009) 10:627-35. doi:10.1038/ni.1734
145. Quann EJ, Liu X, Altan-Bonnet G, Huse M. A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells. Nat Immunol (2011) 12:647- 54. doi:10.1038/ni.2033
146. Alonso R, Mazzeo C, Merida I, Izquierdo M. A new role of diacylglycerol kinase alpha on the secretion of lethal exosomes bearing Fas ligand during activationinduced cell death of T lymphocytes. Biochimie (2007) 89:213-21. doi:10.1016/j.biochi.2006.07.018
147. Alonso R, Mazzeo C, Rodriguez MC, Marsh M, Fraile-Ramos A, Calvo V, et al. Diacylglycerol kinase alpha regulates the formation and polarisation of mature multivesicular bodies involved in the secretion of Fas ligand-containing exosomes in T lymphocytes. Cell Death Differ (2011) 18:1161-73. doi:10.1038/cdd.2010.184
148. Williams MA, Holmes BJ, Sun JC, Bevan MJ. Developing and maintaining protective CD8+ memory T cells. Immunol Rev (2006) 211:146-53. doi:10.1111/j.0105-2896.2006.00389.x
149. Harty JT, Badovinac VP. Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol (2008) 8:107-19. doi:10.1038/nri2251
150. Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity (2011) 35:161-8. doi:10.1016/j.immuni.2011.07.010
151. Shin J, O'Brien TF, Grayson JM, Zhong XP. Differential regulation of primary and memory CD8 T cell immune responses by diacylglycerol kinases. J Immunol (2012) 188:2111-7. doi:10.4049/jimmunol.1102265
152. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, et al. mTOR regulates memory CD8 T-cell differentiation. Nature (2009) 460:108-12. doi:10.1038/nature08155
153. Rao RR, Li Q, Odunsi K, Shrikant PA. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity (2010) 32:67-78. doi:10.1016/j.immuni.2009.10.010
154. Riese MJ, Grewal J, Das J, Zou T, Patil V, Chakraborty AK, et al. Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses. J Biol Chem (2011) 286:5254-65. doi:10.1074/jbc.M110.171884
155. Prinz PU, Mendler AN, Masouris I, Durner L, Oberneder R, Noessner E. High DGK-alpha and disabled MAPK pathways cause dysfunction of human tumorinfiltrating CD8+ T cells that is reversible by pharmacologic intervention. J Immunol (2012) 188:5990-6000. doi:10.4049/jimmunol.1103028
156. Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol (2010) 10:440-52. doi:10.1038/nri2782
157. Rodewald HR, Feyerabend TB. Widespread immunological functions of mast cells: fact or fiction?. Immunity (2012) 37:13-24. doi:10.1016/j.immuni.2012.07.007
158. Olenchock BA, Guo R, Silverman MA, Wu JN, Carpenter JH, Koretzky GA, et al. Impaired degranulation but enhanced cytokine production after Fc epsilonRI stimulation of diacylglycerol kinase zeta-deficient mast cells. J Exp Med (2006) 203:1471-80. doi:10.1084/jem.20052424
159. Liu CH, Machado FS, Guo R, Nichols KE, Burks AW, Aliberti JC, et al. Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii. J Exp Med (2007) 204:781-92. doi:10.1084/jem.20061856