Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants

Nature Immunology

Volumn 16, Issue 11, 2015, Pages 1174-1184

  De Rosa, Veronica ^a,b   Galgani, Mario ^a   Porcellini, Antonio ^c   Colamatteo, Alessandra ^b,d   Santopaolo, Marianna ^c   Zuchegna, Candida ^c   Romano, Antonella ^c   De Simone, Salvatore ^a   Procaccini, Claudio ^a   La Rocca, Claudia ^a   Carrieri, Pietro Biagio ^c   Maniscalco, Giorgia Teresa ^e   Salvetti, Marco ^f   Buscarinu, Maria Chiara ^f   Franzese, Adriana ^c   Mozzillo, Enza ^c   La Cava, Antonio ^g   Matarese, Giuseppe ^d,h  

^a CNR   (Italy)

^b IRCCS FONDAZIONE SANTA LUCIA   (Italy)

^c UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^d UNIVERSITY OF SALERNO   (Italy)

^e CARDARELLI HOSPITAL   (Italy)

^f SAPIENZA UNIVERSITY OF ROME   (Italy)

^g UNIVERSITY OF CALIFORNIA   (United States)

^h IRCCS MULTIMEDICA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CD39 ANTIGEN; CD71 ANTIGEN; ENOLASE 1; GLYCOLYTIC ENZYME; INTERLEUKIN 2; KI 67 ANTIGEN; MESSENGER RNA; MINICHROMOSOME MAINTENANCE PROTEIN 7; RNA 18S; STAT3 PROTEIN; STAT5 PROTEIN; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG; DNA BINDING PROTEIN; ENO1 PROTEIN, HUMAN; ENOLASE; FATTY ACID; FORKHEAD TRANSCRIPTION FACTOR; FOXP3 PROTEIN, HUMAN; LYMPHOCYTE ANTIGEN RECEPTOR; TUMOR MARKER; TUMOR SUPPRESSOR PROTEIN;

ARTICLE; AUTOIMMUNITY; CD4+ CD25+ T LYMPHOCYTE; CONTROLLED STUDY; DNA METHYLATION; EXON; GLYCOLYSIS; HUMAN; HUMAN CELL; IN VITRO STUDY; INSULIN DEPENDENT DIABETES MELLITUS; MITOCHONDRIAL RESPIRATION; MULTIPLE SCLEROSIS; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; SPLICING DEFECT; T LYMPHOCYTE ACTIVATION; ADULT; ALTERNATIVE RNA SPLICING; ANTAGONISTS AND INHIBITORS; CASE CONTROL STUDY; CD4+ T LYMPHOCYTE; CLASSIFICATION; FEMALE; GENE SILENCING; GENETIC VARIATION; GENETICS; IMMUNOLOGY; MALE; METABOLISM; METABOLOME; MIDDLE AGED; OXIDATION REDUCTION REACTION; SIGNAL TRANSDUCTION; YOUNG ADULT;

ADULT; ALTERNATIVE SPLICING; AUTOIMMUNITY; BIOMARKERS, TUMOR; CASE-CONTROL STUDIES; CD4-POSITIVE T-LYMPHOCYTES; DNA-BINDING PROTEINS; EXONS; FATTY ACIDS; FEMALE; FORKHEAD TRANSCRIPTION FACTORS; GENE KNOCKDOWN TECHNIQUES; GENETIC VARIATION; GLYCOLYSIS; HUMANS; IN VITRO TECHNIQUES; MALE; METABOLOME; MIDDLE AGED; MULTIPLE SCLEROSIS, RELAPSING-REMITTING; OXIDATION-REDUCTION; PHOSPHOPYRUVATE HYDRATASE; RECEPTORS, ANTIGEN, T-CELL; RNA, MESSENGER; SIGNAL TRANSDUCTION; T-LYMPHOCYTES, REGULATORY; TUMOR SUPPRESSOR PROTEINS; YOUNG ADULT;

EID: 84945474595     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.3269     Document Type: Article

References (46)

1. Ohkura N., Kitagawa Y., & Sakaguchi S. Development and maintenance of regulatory T cells. Immunity 38, 414-423 (2013
2. Gavin M.A., et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771-775 (2007
3. Lin W., et al. Regulatory T cell development in the absence of functional Foxp3. Nat. Immunol. 8, 359-368 (2007
4. Bilate A.M., & Lafaille J.J. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu. Rev. Immunol. 30, 733-758 (2012
5. Goldstein J.D., et al. Role of cytokines in thymus- versus peripherally derived-regulatory T cell differentiation and function. Front. Immunol. 4, 155 (2013
6. Chen W., et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875-1886 (2003
7. Zheng S.G., Gray J.D., Ohtsuka K., Yamagiwa S., & Horwitz D.A. Generation ex vivo of TGF-â-producing regulatory T cells from CD4+CD25- precursors. J. Immunol. 169, 4183-4189 (2002
8. Walker M.R., et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells. J. Clin. Invest. 112, 1437-1443 (2003
9. Walker M.R., Carson B.D., Nepom G.T., Ziegler S.F., & Buckner J.H. De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells. Proc. Natl. Acad. Sci. USA 102, 4103-4108 (2005
10. Curotto de Lafaille M.A., Lino A.C., Kutchukhidze N., & Lafaille J.J. CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J. Immunol. 173, 7259-7268 (2004
11. Miskov-Zivanov N., Turner M.S., Kane L.P., Morel P.A., & Faeder J.R. The duration of T cell stimulation is a critical determinant of cell fate and plasticity. Sci. Signal. 6, ra97 (2013
12. Van Panhuys N., Klauschen F., & Germain R.N. T-cell-receptor-dependent signal intensity dominantly controls CD4+ T cell polarization in vivo. Immunity 41, 63-74 (2014
13. Turner M.S., Kane L.P., & Morel P.A. Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion. J. Immunol. 183, 4895-4903 (2009
14. Haxhinasto S., Mathis D., & Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205, 565-574 (2008
15. Sauer S., et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl. Acad. Sci. USA 105, 7797-7802 (2008
16. Liang S., et al. Conversion of CD4+CD25- cells into CD4+CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J. Exp. Med. 201, 127-137 (2005
17. Michalek R.D., et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299-3303 (2011
18. Procaccini C., et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33, 929-941 (2010
19. Pearce E.L., & Pearce E.J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633-643 (2013
20. Gerriets V.A., et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 125, 194-207 (2015
21. Chang C.H., et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239-1251 (2013
22. Kaur G., Goodall J.C., Jarvis L.B., & Hill Gaston J.S. Characterization of Foxp3 splice variants in human CD4+ and CD8+ T cells-identification of Foxp3?7 in human regulatory T cells. Mol. Immunol. 48, 321-332 (2010
23. Smith E.L., Finney H.M., Nesbitt A.M., Ramsdell F., & Robinson M.K. Splice variants of human FOXP3 are functional inhibitors of human CD4+ T-cell activation. Immunology 119, 203-211 (2006
24. Allan S.E., et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J. Clin. Invest. 115, 3276-3284 (2005
25. Cheng G., Yu A., & Malek T.R. T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells. Immunol. Rev. 241, 63-76 (2011
26. Carbone F., et al. Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat. Med. 20, 69-74 (2014
27. Wang W., et al. Identification of alpha-enolase as a nuclear DNA-binding protein in the zona fasciculata but not the zona reticularis of the human adrenal cortex. J. Endocrinol. 184, 85-94 (2005
28. Hsu K.W., et al. The activated Notch1 receptor cooperates with α-enolase and MBP-1 in modulating c-myc activity. Mol. Cell. Biol. 28, 4829-4842 (2008
29. Subramanian A., & Miller D.M. Structural analysis of alpha-enolase. Mapping the functional domains involved in down-regulation of the c-myc protooncogene. J. Biol. Chem. 275, 5958-5965 (2000
30. Pancholi V. Multifunctional alpha-enolase: its role in diseases. Cell. Mol. Life Sci. 58, 902-920 (2001
31. Gottschalk R.A., Corse E., & Allison J.P. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 207, 1701-1711 (2010
32. Macintyre A.N., et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61-72 (2014
33. Malek T.R., & Castro I. Interleukin-2 receptor signaling: at the Interface between tolerance and immunity. Immunity 33, 153-165 (2010
34. Carneiro-Sampaio M., & Coutinho A. Early-onset autoimmune disease as a manifestation of primary immunodeficiency. Front. Immunol. 6, 185 (2015
35. King C., Ilic A., Koelsch K., & Sarvetnick N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117, 265-277 (2004
36. Zhou L., et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236-240 (2008
37. Du J., Huang C., Zhou B., & Ziegler S.F. Isoform-specific inhibition of RORα-mediated transcriptional activation by human FOXP3. J. Immunol. 180, 4785-4792 (2008
38. Magg T., Mannert J., Ellwart J.W., Schmid I., & Albert M.H. Subcellular localization of FOXP3 in human regulatory and nonregulatory T cells. Eur. J. Immunol. 42 1627-1638 (2012
39. Maruyama T., Konkel J.E., Zamarron B.F., & Chen W. The molecular mechanisms of Foxp3 gene regulation. Semin. Immunol. 23, 418-423 (2011
40. D'Cruz L.M., & Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol. 6, 1152-1159 (2005
41. Passerini L., et al. STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25- effector T cells. Int. Immunol. 20, 421-431 (2008
42. Fontenot J.D., Rasmussen J.P., Gavin M.A., & Rudensky A.Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142-1151 (2005
43. Kurtzke J.F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33, 1444-1452 (1983
44. Craig M.E., Hattersley A., & Donaghue K.C. Definition, epidemiology and classification of diabetes in children and adolescents. Pediatr. Diabetes 10, 3-12 (2009
45. De Rosa V., et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 26, 241-255 (2007
46. Cuozzo C., et al. DNA damage, homology-directed repair, and DNA methylation. Plos. Genet. 3, e110 (2007