Mitochondrial Ca2+ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function

eLife

Volumn 4, Issue MAY, 2015, Pages

  Yang, Rui ^a   Lirussi, Dario ^a,e   Thornton, Tina M ^a   Jelley Gibbs, Dawn M ^b,f   Diehl, Sean A ^a   Case, Laure K ^a   Madesh, Muniswamy ^c   Taatjes, Douglas J ^d   Teuscher, Cory ^a   Haynes, Laura ^b,g   Rincón, Mercedes ^a  

^a UNIVERSITY OF VERMONT COLLEGE OF MEDICINE   (United States)

^b TRUDEAU INSTITUTE   (United States)

^c TEMPLE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF VERMONT   (United States)

^e HELMHOLTZ CENTRE FOR INFECTION RESEARCH   (Germany)

^f Taconic Inc   (United States)

^g UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; CALCIUM; CD28 ANTIGEN; CD3 ANTIGEN; CD4 ANTIGEN; CYTOCHROME C OXIDASE; INTERLEUKIN 2; INTERLEUKIN 21; INTERLEUKIN 4; INTERLEUKIN 6; MESSENGER RNA; OXIDOREDUCTASE; REACTIVE OXYGEN METABOLITE; STAT3 PROTEIN; TRANSCRIPTION FACTOR NFAT; INTERLEUKIN DERIVATIVE; TXLNA PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CELL ACTIVATION; CELL FUNCTION; CELL VIABILITY; CONFOCAL MICROSCOPY; CONTROLLED STUDY; ELECTRON MICROSCOPY; ENZYME LINKED IMMUNOSORBENT ASSAY; FLOW CYTOMETRY; HYPERPOLARIZATION; IMMUNIZATION; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; MOUSE; NONHUMAN; OXIDATIVE PHOSPHORYLATION; PROTEIN EXPRESSION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION; WESTERN BLOTTING; ANIMAL; C57BL MOUSE; CALCIUM SIGNALING; CD4+ T LYMPHOCYTE; CYTOLOGY; DEFICIENCY; GENETICS; KNOCKOUT MOUSE; MEMBRANE POTENTIAL; METABOLISM; MITOCHONDRIAL MEMBRANE; MITOCHONDRION; PHYSIOLOGY;

ANIMALS; CALCIUM; CALCIUM SIGNALING; CD4-POSITIVE T-LYMPHOCYTES; INTERLEUKIN-6; INTERLEUKINS; MEMBRANE POTENTIALS; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MITOCHONDRIA; MITOCHONDRIAL MEMBRANES; SIGNAL TRANSDUCTION;

EID: 84930633201     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.06376     Document Type: Article

References (100)

1. Acín-Pérez R, Fernández-Silva P, Peleato ML, Pérez-Martos A, Enriquez JA. 2008. Respiratory active mitochondrial supercomplexes. Molecular Cell 32:529-539. doi: 10.1016/j.molcel.2008.10.021.
2. Althoff T, Mills DJ, Popot JL, Kühlbrandt W. 2011. Arrangement of electron transport chain components in bovine mitochondrial supercomplex I1III2IV1. The EMBO Journal 30:4652-4664. doi: 10.1038/emboj.2011.324.
3. Barnden MJ, Allison J, Heath WR, Carbone FR. 1998. Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunology and Cell Biology 76:34-40. doi: 10.1046/j.1440-1711.1998.00709.x.
4. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L Goldberger O, Bogorad RL, Koteliansky V, Mootha VK. 2011. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341-345. doi: 10.1038/nature10234.
5. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235-238. doi: 10. 1038/nature04753.
6. Boulanger MJ, Chow DC, Brevnova EE, Garcia KC. 2003. Hexameric structure and assembly of the interleukin-6/IL- 6 alpha-receptor/gp130 complex. Science 300:2101-2104. doi: 10.1126/science.1083901.
7. Bourillot PY, Aksoy I, Schreiber V, Wianny F, Schulz H, Hummel O, Hubner N, Savatier P. 2009. Novel STAT3 target genes exert distinct roles in the inhibition of mesoderm and endoderm differentiation in cooperation with Nanog. Stem Cells 27:1760-1771. doi: 10.1002/stem.110.
8. Brisac C, TéouléF, Autret A, Pelletier I, Colbè re-Garapin F, Brenner C, Lemaire C, Blondel B. 2010. Calcium flux between the endoplasmic reticulum and mitochondrion contributes to poliovirus-induced apoptosis. Journal of Virology 84:12226-12235. doi: 10.1128/JVI.00994-10.
9. Byun HO, Kim HY, Lim JJ, Seo YH, Yoon G. 2008. Mitochondrial dysfunction by complex II inhibition delays overall cell cycle progression via reactive oxygen species production. Journal of Cellular Biochemistry 104:1747-1759. doi: 10.1002/jcb.21741.
10. Carpenter RL, Lo HW. 2014. STAT3 target genes relevant to human cancers. Cancers 6:897-925. doi: 10.3390/ cancers6020897.
11. Chang CH, Curtis JD, Maggi LB Jr., Faubert B, Villarino AV, O'Sullivan D, Huang SC, van der Windt GJ, Blagih J Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL. 2013. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:1239-1251. doi: 10.1016/j.cell.2013.05.016.
12. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O'Shea JJ. 2006. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proceedings of the National Academy of Sciences of USA 103:8137-8142. doi: 10.1073/pnas.0600666103.
13. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Casarin A Gomes LC, Perales-Clemente E, Salviati L, Fernandez-Silva P, Enriquez JA, Scorrano L. 2013. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155: 160-171. doi: 10.1016/j.cell.2013.08.032.
14. Cox DA, Conforti L, Sperelakis N, Matlib MA. 1993. Selectivity of inhibition of Na(+)-Ca2+ exchange of heart mitochondria by benzothiazepine CGP-37157. Journal of Cardiovascular Pharmacology 21:595-599. doi: 10. 1097/00005344-199304000-00013.
15. de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, Feinberg J, von Bernuth H, Samarina A, Janniè re L, Fieschi C, Stéphan JL, Boileau C, Lyonnet S, Jondeau G, Cormier-Daire V, Le Merrer M, Hoarau C, Lebranchu Y, Lortholary O, Chandesris MO, Tron F, Gambineri E, Bianchi L, Rodriguez-Gallego C, Zitnik SE, Vasconcelos J, Guedes M, Vitor AB, Marodi L, Chapel H, Reid B, Roifman C, Nadal D, Reichenbach J, Caragol I, Garty BZ, Dogu F, Camcioglu Y, Gülle S, Sanal O, Fischer A, Abel L, Stockinger B, Picard C, Casanova JL. 2008. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. The Journal of Experimental Medicine 205:1543-1550. doi: 10.1084/jem.20080321.
16. De Stefani D, Raffaello A, Teardo E, Szabò I, Rizzuto R. 2011. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336-340. doi: 10.1038/nature10230.
17. Delmotte P, Yang B, Thompson MA, Pabelick CM, Prakash YS, Sieck GC. 2012. Inflammation alters regional mitochondrial Ca(2)+ in human airway smooth muscle cells. American Journal of Physiology Cell Physiology 303: C244-C256. doi: 10.1152/ajpcell.00414.2011.
18. Diehl S, Anguita J, Hoffmeyer A, Zapton T, Ihle JN, Fikrig E, Rincón M. 2000. Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity 13:805-815. doi: 10.1016/S1074-7613(00)00078-9.
19. Diehl S, Chow CW, Weiss L, Palmetshofer A, Twardzik T, Rounds L, Serfling E, Davis RJ, Anguita J, Rincón M. 2002. Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation. The Journal of Experimental Medicine 196:39-49. doi: 10.1084/jem.20020026.
20. Diehl SA, Schmidlin H, Nagasawa M, Blom B, Spits H. 2012. IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells. Immunology and Cell Biology 90:802-811. doi: 10.1038/icb.2012.17.
21. Dienz O, Eaton SM, Bond JP, Neveu W, Moquin D, Noubade R, Briso EM, Charland C, Leonard WJ, Ciliberto G Teuscher C, Haynes L, Rincon M. 2009. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. The Journal of Experimental Medicine 206:69-78. doi: 10.1084/jem. 20081571.
22. Dienz O, Eaton SM, Krahl TJ, Diehl S, Charland C, Dodge J, Swain SL, Budd RC, Haynes L, Rincon M. 2007. Accumulation of NFAT mediates IL-2 expression in memory, but not naïve, CD4+ T cells. Proceedings of the National Academy of Sciences of USA 104:7175-7180. doi: 10.1073/pnas.0610442104.
23. Dienz O, Rincon M. 2009. The effects of IL-6 on CD4 T cell responses. Clinical Immunology 130:27-33. doi: 10. 1016/j.clim.2008.08.018.
24. Durant L, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L, Takahashi H, Sun HW, Kanno Y, Powrie F, O'Shea JJ. 2010. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32:605-615. doi: 10.1016/j.immuni.2010.05.003.
25. Erlich TH, Yagil Z, Kay G, Peretz A, Migalovich-Sheikhet H, Tshori S, Nechushtan H, Levi-Schaffer F, Saada A, Razin E. 2014. Mitochondrial STAT3 plays a major role in IgE-antigen-mediated mast cell exocytosis. The Journal of Allergy and Clinical Immunology 134:460-469. doi: 10.1016/j.jaci.2013.12.1075.
26. Feske S. 2007. Calcium signalling in lymphocyte activation and disease. Nature Reviews Immunology 7:690-702. doi: 10.1038/nri2152.
27. Fried SK, Bunkin DA, Greenberg AS. 1998. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. The Journal of Clinical Endocrinology and Metabolism 83:847-850. doi: 10.1210/jcem.83.3.4660.
28. Gomes LC, Di Benedetto G, Scorrano L. 2011. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nature Cell Biology 13:589-598. doi: 10.1038/ncb2220.
29. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE. 2009. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324:1713-1716. doi: 10.1126/science.1171721.
30. Grynkiewicz G, Poenie M, Tsien RY. 1985. A new generation of Ca2+ indicators with greatly improved fluorescence properties. The Journal of Biological Chemistry 260:3440-3450.
31. Hackenbrock CR. 1966. Ultrastructural bases for metabolically linked mechanical activity in mitochondria. I. Reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria. The Journal of Cell Biology 30:269-297. doi: 10.1083/jcb.30.2.269.
32. Hajnóczky G, Robb-Gaspers LD, Seitz MB, Thomas AP. 1995. Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82:415-424. doi: 10.1016/0092-8674(95)90430-1.
33. Hatle KM, Gummadidala P, Navasa N, Bernardo E, Dodge J, Silverstrim B, Fortner K, Burg E, Suratt BT, Hammer J Radermacher M, Taatjes DJ, Thornton T, Anguita J, Rincon M. 2013. MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations. Molecular and Cellular Biology 33:2302-2314. doi: 10.1128/MCB.00189-13.
34. Heijink IH, Vellenga E, Borger P, Postma DS, de Monchy JG, Kauffman HF. 2002. Interleukin-6 promotes the production of interleukin-4 and interleukin-5 by interleukin-2-dependent and -independent mechanisms in freshly isolated human T cells. Immunology 107:316-324. doi: 10.1046/j.1365-2567.2002.01501.x.
35. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. 2003. Principles of interleukin (IL)-6- type cytokine signalling and its regulation. The Biochemical Journal 374:1-20. doi: 10.1042/BJ20030407.
36. Heusch G, Musiolik J, Gedik N, Skyschally A. 2011. Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circulation Research 109: 1302-1308. doi: 10.1161/CIRCRESAHA.111.255604.
37. Hirano T, Ishihara K, Hibi M. 2000. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19:2548-2556. doi: 10.1038/sj.onc.1203551.
38. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whitney AR Voyich JM, Musser JM, Woellner C, Schäffer AA, Puck JM, Grimbacher B. 2007. STAT3 mutations in the hyper- IgE syndrome. The New England Journal of Medicine 357:1608-1619. doi: 10.1056/NEJMoa073687.
39. Hoth M, Fanger CM, Lewis RS. 1997. Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. The Journal of Cell Biology 137:633-648. doi: 10.1083/jcb.137.3.633.
40. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. 2006. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121-1133. doi: 10.1016/j.cell.2006.07.035.
41. Jiao H, Tóth B, Erdos M, Fransson I, Rákóczi E, Balogh I, Magyarics Z, Dérfalvi B, Csorba G, Szaflarska A Megarbane A, Akatcherian C, Dbaibo G, Rajnavölgyi E, Hammarström L, Kere J, Lefranc G, Maródi L. 2008. Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups. Molecular Immunology 46:202-206. doi: 10.1016/j.molimm.2008.07.001.
42. Kaplan MH, Glosson NL, Stritesky GL, Yeh N, Kinzfogl J, Rohrabaugh SL, Goswami R, Pham D, Levy DE Brutkiewicz RR, Blum JS, Cooper S, Hangoc G, Broxmeyer HE. 2011. STAT3-dependent IL-21 production from T helper cells regulates hematopoietic progenitor cell homeostasis. Blood 117:6198-6201. doi: 10.1182/blood- 2011-02-334367.
43. Kim HP, Korn LL, Gamero AM, Leonard WJ. 2005. Calcium-dependent activation of interleukin-21 gene expression in T cells. The Journal of Biological Chemistry 280:25291-25297. doi: 10.1074/jbc.M501459200.
44. Kim MS, Usachev YM. 2009. Mitochondrial Ca2+ cycling facilitates activation of the transcription factor NFAT in sensory neurons. The Journal of Neuroscience 29:12101-12114. doi: 10.1523/JNEUROSCI.3384-09.2009.
45. Kirichok Y, Krapivinsky G, Clapham DE. 2004. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360-364. doi: 10.1038/nature02246.
46. Kishimoto T. 2005. Interleukin-6: from basic science to medicine-40 years in immunology. Annual Review of Immunology 23:1-21. doi: 10.1146/annurev.immunol.23.021704.115806.
47. Lachance C, Goupil S, Leclerc P. 2013. Stattic V, a STAT3 inhibitor, affects human spermatozoa through regulation of mitochondrial activity. Journal of Cellular Physiology 228:704-713. doi: 10.1002/jcp.24215.
48. Lee PP, Fitzpatrick DR, Beard C, Jessup HK, Lehar S, Makar KW, Pérez-Melgosa M, Sweetser MT, Schlissel MS Nguyen S, Cherry SR, Tsai JH, Tucker SM, Weaver WM, Kelso A, Jaenisch R, Wilson CB. 2001. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15:763-774. doi: 10.1016/ S1074-7613(01)00227-8.
49. Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT, Cao X. 2003. GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction. The EMBO Journal 22:1325-1335. doi: 10.1093/ emboj/cdg135.
50. Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, Fulcher DA, Tangye SG, Cook MC. 2008. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. The Journal of Experimental Medicine 205:1551-1557. doi: 10.1084/jem.20080218.
51. Mallilankaraman K, Cárdenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenár T, Csordás G, Madireddi P Yang J, Müller M, Miller R, Kolesar JE, MolgóJ, Kaufman B, Hajnóczky G, Foskett JK, Madesh M. 2012a. MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nature Cell Biology 14:1336-1343. doi: 10.1038/ncb2622.
52. Mallilankaraman K, Doonan P, Cárdenas C, Chandramoorthy HC, Müller M, Miller R, Hoffman NE, Gandhirajan RK MolgóJ, Birnbaum MJ, Rothberg BS, Mak DO, Foskett JK, Madesh M. 2012b. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 151:630-644. doi: 10.1016/j.cell. 2012.10.011.
53. Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O'Malley JT, Kapur R, Levy DE, Kansas GS, Kaplan MH. 2007. Stat3 and Stat4 direct development of IL-17-secreting Th cells. The Journal of Immunology 178:4901-4907. doi: 10.4049/jimmunol.178.8.4901.
54. Matlib MA, Zhou Z, Knight S, Ahmed S, Choi KM, Krause-Bauer J, Phillips R, Altschuld R, Katsube Y, Sperelakis N Bers DM. 1998. Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes. The Journal of Biological Chemistry 273: 10223-10231. doi: 10.1074/jbc.273.17.10223.
55. Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, Theurich S, Hausen AC, Schmitz J, Brönneke HS Estevez E, Allen TL, Mesaros A, Partridge L, Febbraio MA, Chawla A, Wunderlich FT, Brüning JC. 2014. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nature Immunology 15:423-430. doi: 10.1038/ni.2865.
56. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML Davis J, Hsu A, Asher AI, O'Shea J, Holland SM, Paul WE, Douek DC. 2008. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452:773-776. doi: 10.1038/nature06764.
57. Minegishi Y, Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, Agematsu K, Yamada M, Kawamura N, Ariga T Tsuge I, Karasuyama H. 2009. Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome. The Journal of Experimental Medicine 206:1291-1301. doi: 10.1084/jem.20082767.
58. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A Karasuyama H. 2007. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448:1058-1062. doi: 10.1038/nature06096.
59. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. 1997. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. The Journal of Clinical Endocrinology and Metabolism 82:4196-4200. doi: 10.1210/jcem.82.12.4450.
60. Nagaleekar VK, Diehl SA, Juncadella I, Charland C, Muthusamy N, Eaton S, Haynes L, Garrett-Sinha LA, Anguita J Rincón M. 2008. IP3 receptor-mediated Ca2+ release in naive CD4 T cells dictates their cytokine program. The Journal of Immunology 181:8315-8322. doi: 10.4049/jimmunol.181.12.8315.
61. Nita II, Hershfinkel M, Fishman D, Ozeri E, Rutter GA, Sensi SL, Khananshvili D, Lewis EC, Sekler I. 2012. The mitochondrial Na+/Ca2+ exchanger upregulates glucose dependent Ca2+ signalling linked to insulin secretion. PLoS One 7:e46649. doi: 10.1371/journal.pone.0046649.
62. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM Dong C. 2007. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448: 480-483. doi: 10.1038/nature05969.
63. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, Dong C. 2008. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29:138-149. doi: 10.1016/j.immuni.2008.05.009.
64. Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, Parnis J, Nolte C, Fishman D, Shoshan-Barmatz V Herrmann S, Khananshvili D, Sekler I. 2010. NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proceedings of the National Academy of Sciences of USA 107:436-441. doi: 10.1073/pnas.0908099107.
65. Pasare C, Medzhitov R. 2003. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033-1036. doi: 10.1126/science.1078231.
66. Pearce EL, Poffenberger MC, Chang CH, Jones RG. 2013. Fueling immunity: insights into metabolism and lymphocyte function. Science 342:1242454. doi: 10.1126/science.1242454.
67. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y. 2009. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460:103-107. doi: 10.1038/nature08097.
68. Petruzzelli M, Schweiger M, Schreiber R, Campos-Olivas R, Tsoli M, Allen J, Swarbrick M, Rose-John S, Rincon M Robertson G, Zechner R, Wagner EF. 2014. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metabolism 20:433-447. doi: 10.1016/j.cmet.2014.06.011.
69. Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, Ciliberto G, Rodan GA, Costantini F. 1994. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. The EMBO Journal 13: 1189-1196.
70. Quintana A, Schwindling C, Wenning AS, Becherer U, Rettig J, Schwarz EC, Hoth M. 2007. T cell activation requires mitochondrial translocation to the immunological synapse. Proceedings of the National Academy of Sciences of USA 104:14418-14423. doi: 10.1073/pnas.0703126104.
71. Rao A. 1994. NF-ATp: a transcription factor required for the co-ordinate induction of several cytokine genes. Immunology Today 15:274-281. doi: 10.1016/0167-5699(94)90007-8.
72. Rengarajan J, Mowen KA, McBride KD, Smith ED, Singh H, Glimcher LH. 2002. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. The Journal of Experimental Medicine 195: 1003-1012. doi: 10.1084/jem.20011128.
73. Renner ED, Rylaarsdam S, Anover-Sombke S, Rack AL, Reichenbach J, Carey JC, Zhu Q, Jansson AF, Barboza J Schimke LF, Leppert MF, Getz MM, Seger RA, Hill HR, Belohradsky BH, Torgerson TR, Ochs HD. 2008. Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome. The Journal of Allergy and Clinical Immunology 122: 181-187. doi: 10.1016/j.jaci.2008.04.037.
74. Rincón M, Anguita J, Nakamura T, Fikrig E, Flavell RA. 1997. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. The Journal of Experimental Medicine 185:461-469. doi: 10.1084/jem. 185.3.461.
75. Rizzuto R, De Stefani D, Raffaello A, Mammucari C. 2012. Mitochondria as sensors and regulators of calcium signalling. Nature Reviews Molecular Cell Biology 13:566-578. doi: 10.1038/nrm3412.
76. Schägger H. 1995. Native electrophoresis for isolation of mitochondrial oxidative phosphorylation protein complexes. Methods in Enzymology 260:190-202.
77. Schieke SM, McCoy JP Jr., Finkel T. 2008. Coordination of mitochondrial bioenergetics with G1 phase cell cycle progression. Cell Cycle 7:1782-1787. doi: 10.4161/cc.7.12.6067.
78. Schust J, Sperl B, Hollis A, Mayer TU, Berg T. 2006. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chemistry & Biology 13:1235-1242. doi: 10.1016/j.chembiol.2006.09.018.
79. Schwindling C, Quintana A, Krause E, Hoth M. 2010. Mitochondria positioning controls local calcium influx in T cells. The Journal of Immunology 184:184-190. doi: 10.4049/jimmunol.0902872.
80. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, Wang CR, Schumacker PT, Licht JD, Perlman H Bryce PJ, Chandel NS. 2013. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38:225-236. doi: 10.1016/j.immuni.2012.10.020.
81. Shanmughapriya S, Rajan S, Hoffman NE, Zhang X, Guo S, Kolesar JE, Hines KJ, Ragheb J, Jog NR, Caricchio R Baba Y, Zhou Y, Kaufman BA, Cheung JY, Kurosaki T, Gill DL, Madesh M. 2015. Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU. Science Signaling 8:ra23. doi: 10.1126/scisignal.2005673.
82. Shulman Z, Gitlin AD, Weinstein JS, Lainez B, Esplugues E, Flavell RA, Craft JE, Nussenzweig MC. 2014. Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 345:1058-1062. doi: 10.1126/ science.1257861.
83. Smart N, Mojet MH, Latchman DS, Marber MS, Duchen MR, Heads RJ. 2006. IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes. Cardiovascular Research 69:164-177. doi: 10.1016/j.cardiores.2005.08.017.
84. Soboloff J, Rothberg BS, Madesh M, Gill DL. 2012. STIM proteins: dynamic calcium signal transducers. Nature Reviews Molecular Cell Biology 13:549-565. doi: 10.1038/nrm3414.
85. Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, Nakano K, Hirshman MF Tseng YH, Goodyear LJ. 2013. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. The Journal of Clinical Investigation 123:215-223. doi: 10.1172/JCI62308.
86. Starkov AA. 2010. The molecular identity of the mitochondrial Ca2+ sequestration system. The FEBS Journal 277: 3652-3663. doi: 10.1111/j.1742-4658.2010.07756.x.
87. Steward-Tharp SM, Laurence A, Kanno Y, Kotlyar A, Villarino AV, Sciume G, Kuchen S, Resch W, Wohlfert EA Jiang K, Hirahara K, Vahedi G, Sun HW, Feigenbaum L, Milner JD, Holland SM, Casellas R, Powrie F, O'Shea JJ. 2014. A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3. Blood 123:2978-2987. doi: 10.1182/blood-2013-09-523167.
88. Suto A, Kashiwakuma D, Kagami S, Hirose K, Watanabe N, Yokote K, Saito Y, Nakayama T, Grusby MJ, Iwamoto I Nakajima H. 2008. Development and characterization of IL-21-producing CD4+ T cells. The Journal of Experimental Medicine 205:1369-1379. doi: 10.1084/jem.20072057.
89. Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S. 1998. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. The Journal of Immunology 161:4652-4660.
90. Tammineni P, Anugula C, Mohammed F, Anjaneyulu M, Larner AC, Sepuri NB. 2013. The import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain. The Journal of Biological Chemistry 288:4723-4732. doi: 10.1074/jbc.M112.378984.
91. Tanaka T, Kishimoto T. 2012. Targeting interleukin-6: all the way to treat autoimmune and inflammatory diseases. International Journal of Biological Sciences 8:1227-1236. doi: 10.7150/ijbs.4666.
92. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL. 2012. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36:68-78. doi: 10.1016/ j.immuni.2011.12.007.
93. Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, Kales A, Chrousos GP. 2000. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. The Journal of Clinical Endocrinology and Metabolism 85:1151-1158. doi: 10.1210/jcem.85.3.6484.
94. Wang R, Green DR. 2012. Metabolic checkpoints in activated T cells. Nature Immunology 13:907-915. doi: 10. 1038/ni.2386.
95. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, Moh A, Moghaddas S, Chen Q, Bobbili S, Cichy J, Dulak J, Baker DP, Wolfman A, Stuehr D, Hassan MO, Fu XY Avadhani N, Drake JI, Fawcett P, Lesnefsky EJ, Larner AC. 2009. Function of mitochondrial Stat3 in cellular respiration. Science 323:793-797. doi: 10.1126/science.1164551.
96. Winge DR. 2012. Sealing the mitochondrial respirasome. Molecular and Cellular Biology 32:2647-2652. doi: 10. 1128/MCB.00573-12.
97. Wu M, Neilson A, Swift AL, Moran R, Tamagnine J, Parslow D, Armistead S, Lemire K, Orrell J, Teich J, Chomicz S Ferrick DA. 2007. Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. American Journal of Physiology Cell Physiology 292:C125-C136. doi: 10.1152/ajpcell.00247.2006.
98. Yip L, Woehrle T, Corriden R, Hirsh M, Chen Y, Inoue Y, Ferrari V, Insel PA, Junger WG. 2009. Autocrine regulation of T-cell activation by ATP release and P2X7 receptors. FASEB Journal 23:1685-1693. doi: 10.1096/fj.08-126458.
99. Zhang Q, Raje V, Yakovlev VA, Yacoub A, Szczepanek K, Meier J, Derecka M, Chen Q, Hu Y, Sisler J, Hamed H Lesnefsky EJ, Valerie K, Dent P, Larner AC. 2013. Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. The Journal of Biological Chemistry 288:31280-31288. doi: 10.1074/jbc.M113. 505057.
100. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. 2007. IL-6 programs T (H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunology 8:967-974. doi: 10.1038/ni1488.