Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response

Molecular Systems Biology

Volumn 6, Issue , 2010, Pages

  Feinerman, Ofer ^a   Jentsch, Garrit ^b   Tkach, Karen E ^a   Coward, Jesse W ^a   Hathorn, Matthew M ^a   Sneddon, Michael W ^b   Emonet, Thierry ^b   Smith, Kendall A ^c   Altan Bonnet, Grégoire ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b YALE UNIVERSITY   (United States)

^c WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

cellular heterogeneity; computer modeling; IL 2 signaling; immunology; regulatory T cells

Indexed keywords

INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR ALPHA; STAT5 PROTEIN; IL2RA PROTEIN, MOUSE;

ANIMAL EXPERIMENT; ARTICLE; CELL ACTIVATION; CELL PROLIFERATION; CELL SURVIVAL; COMPUTER MODEL; CONTROLLED STUDY; EFFECTOR CELL; IMMUNE RESPONSE; MOUSE; NONHUMAN; PLASTICITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY MECHANISM; REGULATORY T LYMPHOCYTE; UPREGULATION; ANIMAL; BIOLOGICAL MODEL; C57BL MOUSE; CELL CULTURE; CELLULAR IMMUNITY; COCULTURE; ENZYME LINKED IMMUNOSORBENT ASSAY; HELPER CELL; IMMUNOLOGY; METABOLISM; METHODOLOGY; PHYSIOLOGY; SINGLE CELL ANALYSIS; STAINING; TRANSGENIC MOUSE; VALIDATION STUDY;

ANIMALS; CELLS, CULTURED; COCULTURE TECHNIQUES; ENZYME-LINKED IMMUNOSORBENT ASSAY; IMMUNITY, CELLULAR; INTERLEUKIN-2; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; MICE; MICE, INBRED C57BL; MICE, TRANSGENIC; MODELS, BIOLOGICAL; SINGLE-CELL ANALYSIS; STAINING AND LABELING; T-LYMPHOCYTES, HELPER-INDUCER; T-LYMPHOCYTES, REGULATORY;

EID: 78649875958     PISSN: 17444292     EISSN: 17444292     Source Type: Journal    
DOI: 10.1038/msb.2010.90     Document Type: Article

References (59)

1. Altan-Bonnet G, Germain RN (2005) Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLoS Biol 3: e356
2. Barthlott T, Moncrieffe H, Veldhoen M, Atkins CJ, Christensen J, O'Garra A, Stockinger B (2005) CD25+ CD4+ Tcells compete with naive CD4+ Tcells for IL-2 and exploit it for the induction of IL-10 production. Int Immunol 17:279-288
3. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420:502-507
4. Blinov ML, Faeder JR, Goldstein B, Hlavacek WS (2004) BioNetGen: software for rule-based modeling of signal transduction based on the interactions of molecular domains. Bioinformatics 20:3289-3291
5. Brand OJ, Lowe CE, Heward JM, Franklyn JA, Cooper JD, Todd JA, Gough SC (2007) Association of the interleukin-2 receptor alpha (IL-2Ralpha)/CD25 gene region with Graves' disease using a multilocus test and tag SNPs. Clin Endocrinol (Oxf) 66:508-512
6. Brandenburg S, Takahashi T, de la Rosa M, Janke M, Karsten G, Muzzulini T, Orinska Z, Bulfone-Paus S, Scheffold A (2008) IL-2 induces in vivo suppression by CD4 (+) CD25 (+) Foxp3 (+) regulatory Tcells. Eur J Immunol 38:1643-1653
7. Burroughs NJ, Miguel Paz Mendes de Oliveira B, Adrego Pinto A (2006) Regulatory T cell adjustment of quorum growth thresholds and the control of local immune responses. J Theor Biol 241:134-141
8. Busse D, de la Rosa M, Hobiger K, Thurley K, Flossdorf M, Scheffold A, Hofer T (2010) Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proc Natl Acad Sci U S A 107:3058-3063
9. Cantrell DA, Smith KA (1984) The interleukin-2 T-cell system: a new cell growth model. Science 224:1312-1316
10. Chen Y, Inobe J, Kuchroo VK, Baron JL, Janeway Jr CA., Weiner HL (1996) Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells. Proc Natl Acad Sci U S A 93:388-391
11. Davis MM, Boniface JJ, Reich Z, Lyons D, Hampl J, Arden B, Chien Y (1998) Ligand recognition by alpha beta Tcell receptors. Annu Rev Immunol 16:523-544
12. Duprez V, Cornet V, Dautry-Varsat A (1988) Down-regulation of high affinity interleukin 2 receptors in a human tumor T cell line. Interleukin 2 increases the rate of surface receptor decay. J Biol Chem 263:12860-12865
13. Duprez V, Dautry-Varsat A (1986) Receptor-mediated endocytosis of interleukin 2 in a human tumor T cell line. Degradation of interleukin 2 and evidence for the absence of recycling of interleukin receptors. J Biol Chem 261:15450-15454
14. Duprez V, Ferrer M, Cornet V, Olive D, Dautry-Varsat A (1991) Modulation of interleukin 2 internalization and interleukin 2-dependent cell growth by antireceptor antibodies. J Biol Chem 266:1497-1501
15. Feinerman O, Veiga J, Dorfman JR, Germain RN, Altan-Bonnet G (2008) Variability and robustness in Tcell activation from regulated heterogeneity in protein levels. Science 321:1081-1084
16. Forsten KE, Lauffenburger DA (1994) The role of low-affinity interleukin-2 receptors in autocrine ligand binding: alternative mechanisms for enhanced binding effect. Mol Immunol 31:739-751
17. George TC, Bilsborough J, Viney JL, Norment AM (2003) High antigen dose and activated dendritic cells enable Th cells to escape regulatory T cell-mediated suppression in vitro. Eur J Immunol 33:502-511
18. Hemar A, Subtil A, Lieb M, Morelon E, Hellio R, Dautry-Varsat A (1995) Endocytosis of interleukin 2 receptors in human T lymphocytes: distinct intracellular localization and fate of the receptor alpha, beta, and gamma chains. J Cell Biol 129:55-64
19. Horak I, Lohler J, Ma A, Smith KA (1995) Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance. Immunol Rev 148:35-44
20. Ihle JN (2001) The Stat family in cytokine signaling. Curr Opin Cell Biol 13:211-217
21. Irvine DJ, Purbhoo MA, Krogsgaard M, Davis MM (2002) Direct observation of ligand recognition by Tcells. Nature 419:845-849
22. Kemp ML, Wille L, Lewis CL, Nicholson LB, Lauffenburger DA (2007) Quantitative network signal combinations downstream of TCR activation can predict IL-2 production response. J Immunol 178:4984-4992
23. Kim HP, Imbert J, Leonard WJ (2006) Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev 17:349-366
24. Kim HP, Kelly J, Leonard WJ (2001) The basis for IL-2-induced IL-2 receptor alpha chain gene regulation: importance of two widely separated IL-2 response elements. Immunity 15:159-172
25. Krogsgaard M, Prado N, Adams EJ, He XL, Chow DC, Wilson DB, Garcia KC, Davis MM (2003) Evidence that structural rearrangements and/or flexibility during TCR binding can contribute to Tcell activation. Mol Cell 12:1367-1378
26. Krutzik PO, Clutter MR, Nolan GP (2005) Coordinate analysis of murine immune cell surface markers and intracellular phosphoproteins by flow cytometry. J Immunol 175:2357-2365
27. Lenardo MJ (1991) Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature 353:858-861
28. Lin JX, Leonard WJ (2000) The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 19:2566-2576
29. Long M, Adler AJ (2006) Cutting edge: paracrine, but not autocrine, IL-2 signaling is sustained during early antiviral CD4 Tcell response. J Immunol 177:4257-4261
30. Lund JM, Hsing L, Pham TT, Rudensky AY (2008) Coordinationofearly protective immunity to viral infection by regulatory Tcells. Science 320:1220-1224
31. O'Gorman WE, Dooms H, Thorne SH, Kuswanto WF, Simonds EF, Krutzik PO, Nolan GP, Abbas AK (2009) The initial phase of an immune response functions to activate regulatory T cells. J Immunol 183:332-339
32. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ (2007) CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 8:1353-1362
33. Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033-1036
34. Pillet AH, Lavergne V, Pasquier V, Gesbert F, Thèze J, Rose T (2010) IL-2 induces conformational changes in its preassembled receptor core, which then migrates in lipid raft and binds to the cytoskeleton meshwork. J Mol Biol 403:671-692
35. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531-562
36. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151-1164
37. Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T (2009) Regulatory T cells: how do they suppress immune responses? Int Immunol 21:1105-1111
38. Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I (1991) Development and function of Tcells in mice rendered interleukin-2 deficient by gene targeting. Nature 352:621-624
39. Schulz EG, Mariani L, Radbruch A, Hofer T (2009) Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12. Immunity 30:673-683
40. Seder RA, Paul WE, Davis MM, Fazekas de St Groth B (1992) The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med 176:1091-1098
41. Shevach EM (2009) Mechanismsof foxp3+ Tregulatory cell-mediated suppression. Immunity 30:636-645
42. Smith KA (1984) Interleukin 2. Annu Rev Immunol 2:319-333
43. Smith KA, Cantrell DA (1985) Interleukin 2 regulates its own receptors. Proc Natl Acad Sci USA 82:864-868
44. Sojka DK, Bruniquel D, Schwartz RH, Singh NJ (2004) IL-2 secretion by CD4+ T cells in vivo is rapid, transient, and influenced by TCR-specific competition. J Immunol 172:6136-6143
45. Sojka DK, Hughson A, Sukiennicki TL, Fowell DJ (2005) Early kinetic window of target T cell susceptibility to CD25+ regulatory T cell activity. J Immunol 175:7274-7280
46. Stephens LA, Gray D, Anderton SM (2005) CD4+CD25+ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity. Proc Natl Acad Sci U S A 102:17418-17423
47. Surette MG, Miller MB, Bassler BL (1999) Quorum sensing in Escherichia coli, Salmonella typhimurium, and Vibrio harveyi: a new family of genes responsible for autoinducer production. Proc Natl Acad Sci U S A 96:1639-1644
48. Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E, Matsuyama T, Schmits R, Simard JJ, Ohashi PS, Griesser H, Taniguchi T, Paige CJ, Mak TW (1995) Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268:1472-1476
49. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, Piccirillo CA, Salomon BL, Bluestone JA (2008) Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28:687-697
50. Thornton AM, Shevach EM (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287-296
51. Tomlin CJ, Axelrod JD (2007) Biology by numbers: mathematical modelling in developmental biology. Nat Rev Genet 8:331-340
52. Tran DQ, Glass DD, Uzel G, Darnell DA, Spalding C, Holland SM, Shevach EM (2009) Analysis of adhesion molecules, target cells, and role of IL-2 in human FOXP3+ regulatory T cell suppressor function. J Immunol 182:2929-2938
53. Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, Widmer B, Jones R, Ring SM, McArdle W, Pembrey ME, Strachan DP, Dunger DB, Twells RC, Clayton DG, Todd JA (2005) Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 76:773-779
54. Villarino AV, Tato CM, Stumhofer JS, Yao Z, Cui YK, Hennighausen L, O'Shea JJ, Hunter CA (2007) Helper Tcell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J Exp Med 204:65-71
55. von Boehmer H (2005) Mechanisms of suppression by suppressor T cells. Nat Immunol 6:338-344
56. Wang HM, Smith KA (1987) The interleukin 2 receptor. Functional consequences of its bimolecular structure. J Exp Med 166:1055-1069
57. Webster KE, WaltersS, Kohler RE, MrkvanT, BoymanO, Surh CD, Grey ST, Sprent J (2009) In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med 206:751-760
58. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW (1995) Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3:521-530
59. Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, Gonzalez-Munoz A, Clark J, Veijola R, Cubbon R, Chen SL, Rosa R, Cumiskey AM, Serreze DV, Gregory S, Rogers J, Lyons PA, Healy B, Smink LJ, Todd JA et al (2007) Interleukin-2 gene variation impairs regulatory Tcell function and causes autoimmunity. Nat Genet 39:329-337