Immune Netw.  2011 Feb;11(1):1-10. 10.4110/in.2011.11.1.1.

Seeing Is Believing: Illuminating the Source of In Vivo Interleukin-7

• Kim GY
• Hong C
• Park JH

• KMID: 2150689
• DOI: http://doi.org/10.4110/in.2011.11.1.1

Abstract

Interleukin-7 (IL-7) is an essential cytokine for T cells. However, IL-7 is not produced by T cells themselves such that T cells are dependent on extrinsic IL-7. In fact, in the absence of IL-7, T cell development in the thymus as well as survival of naive T cells in the periphery is severely impaired. Furthermore, modulating IL-7 availability in vivo either by genetic means or other experimental approaches determines the size, composition and function of the T cell pool. Consequently, understanding IL-7 expression is critical for understanding T cell immunity. Until most recently, however, the spatiotemporal expression of in vivo IL-7 has remained obscured. Shortage of such information was partly due to scarce expression of IL-7 itself but mainly due to the lack of adequate reagents to monitor IL-7 expression in vivo. This situation dramatically changed with a recent rush of four independent studies that describe the generation and characterization of IL-7 reporter mice, all utilizing bacterial artificial chromosome transgene technology. The emerging consensus of these studies confirmed thymic stromal cells as the major producers of IL-7 but also identified IL-7 reporter activities in various peripheral tissues including skin, intestine and lymph nodes. Strikingly, developmental and environmental cues actively modulated IL-7 reporter activities in vivo suggesting that IL-7 regulation might be a new mechanism of shaping T cell development and homeostasis. Collectively, the availability of these new tools opens up new venues to assess unanswered questions in IL-7 biology in T cells and beyond.

Keyword

Thymus; T cells; Homeostasis; Bacterial artificial chromosome

MeSH Terms

Animals
Biology
Chromosomes, Artificial, Bacterial
Consensus
Cues
Homeostasis
Indicators and Reagents
Interleukin-7
Intestines
Lymph Nodes
Mice
Organothiophosphorus Compounds
Skin
Stromal Cells
T-Lymphocytes
Thymus Gland
Transgenes
Indicators and Reagents
Interleukin-7
Organothiophosphorus Compounds

Figure

• 

  Figure 1 Schematic representation of the BAC constructs for IL-7 reporter mice. Endogenous wildtype IL-7 locus is shown at the top. Alves et al. (51) generated BAC transgenic mice encoding the yellow fluorescent protein (YFP) under the control of the IL-7 promoter. The YFP gene was inserted by homologous recombination downstream of the ATG transcriptional start codon of exon 1 of the IL-7 locus. Repass et al. (52) generated two BAC transgenic mice where IL-7 regulatory elements drive either Cre recombinase (IL-7.Cre) or human CD25 (IL-7.hCD25) reporter expression. Mazzucchelli et al. (53) generated BAC transgenic mice encoding the enhanced cyan fluorescence protein (ECFP) under the control of the IL-7 promoter (IL7promECFP). The exon 1 sequence, encoding the signal peptide was replaced with the Ecfp cDNA sequence starting after the ATG start site. Shalapour et al. (54) generated BAC transgenic mice simultaneously expressing enhanced green fluorescent protein (G), recombinase Cre (C), the human diphtheria toxin receptor (D) and click beetle green luciferase 99 (L) under control of the IL-7 promoter (IL-7GCDL). E1~E5: Exon 1~Exon 5. UTR: Untranslated region.

Reference

1. Namen AE, Schmierer AE, March CJ, Overell RW, Park LS, Urdal DL, Mochizuki DY. B cell precursor growth-promoting activity. Purification and characterization of a growth factor active on lymphocyte precursors. J Exp Med. 1988. 167:988–1002.

2. Peschon JJ, Morrissey PJ, Grabstein KH, Ramsdell FJ, Maraskovsky E, Gliniak BC, Park LS, Ziegler SF, Williams DE, Ware CB, Meyer JD, Davison BL. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med. 1994. 180:1955–1960.

3. von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med. 1995. 181:1519–1526.

4. Schluns KS, Kieper WC, Jameson SC, Lefrançois L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat Immunol. 2000. 1:426–432.

5. Tan JT, Dudl E, LeRoy E, Murray R, Sprent J, Weinberg KI, Surh CD. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci U S A. 2001. 98:8732–8737.

6. Park JH, Adoro S, Guinter T, Erman B, Alag AS, Catalfamo M, Kimura MY, Cui Y, Lucas PJ, Gress RE, Kubo M, Hennighausen L, Feigenbaum L, Singer A. Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat Immunol. 2010. 11:257–264.

7. Puel A, Ziegler SF, Buckley RH, Leonard WJ. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet. 1998. 20:394–397.

8. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993. 73:147–157.

9. Witte PL, Burrows PD, Kincade PW, Cooper MD. Characterization of B lymphocyte lineage progenitor cells from mice with severe combined immune deficiency disease (SCID) made possible by long term culture. J Immunol. 1987. 138:2698–2705.

10. Akashi K, Kondo M, von Freeden-Jeffry U, Murray R, Weissman IL. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell. 1997. 89:1033–1041.

11. Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature. 2003. 426:671–676.

12. Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood. 2008. 111:2101–2111.

13. Vivien L, Benoist C, Mathis D. T lymphocytes need IL-7 but not IL-4 or IL-6 to survive in vivo. Int Immunol. 2001. 13:763–768.

14. Rathmell JC, Farkash EA, Gao W, Thompson CB. IL-7 enhances the survival and maintains the size of naive T cells. J Immunol. 2001. 167:6869–6876.

15. Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity. 2008. 29:848–862.

16. Ku CC, Murakami M, Sakamoto A, Kappler J, Marrack P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science. 2000. 288:675–678.

17. Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med. 2002. 195:1523–1532.

18. Kieper WC, Tan JT, Bondi-Boyd B, Gapin L, Sprent J, Ceredig R, Surh CD. Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J Exp Med. 2002. 195:1533–1539.

19. Schluns KS, Williams K, Ma A, Zheng XX, Lefrançois L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol. 2002. 168:4827–4831.

20. Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009. 9:480–490.

21. Witthuhn BA, Silvennoinen O, Miura O, Lai KS, Cwik C, Liu ET, Ihle JN. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994. 370:153–157.

22. Maraskovsky E, O'Reilly LA, Teepe M, Corcoran LM, Peschon JJ, Strasser A. Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1-/- mice. Cell. 1997. 89:1011–1019.

23. Chehtane M, Khaled AR. Interleukin-7 mediates glucose utilization in lymphocytes through transcriptional regulation of the hexokinase II gene. Am J Physiol Cell Physiol. 2010. 298:C1560–C1571.

24. Khaled AR, Bulavin DV, Kittipatarin C, Li WQ, Alvarez M, Kim K, Young HA, Fornace AJ, Durum SK. Cytokine-driven cell cycling is mediated through Cdc25A. J Cell Biol. 2005. 169:755–763.

25. Jiang Q, Li WQ, Aiello FB, Mazzucchelli R, Asefa B, Khaled AR, Durum SK. Cell biology of IL-7, a key lymphotrophin. Cytokine Growth Factor Rev. 2005. 16:513–533.

26. Chowdhury D, Sen R. Transient IL-7/IL-7R signaling provides a mechanism for feedback inhibition of immunoglobulin heavy chain gene rearrangements. Immunity. 2003. 18:229–241.

27. Maki K, Sunaga S, Ikuta K. The V-J recombination of T cell receptor-gamma genes is blocked in interleukin-7 receptor-deficient mice. J Exp Med. 1996. 184:2423–2427.

28. Meier D, Bornmann C, Chappaz S, Schmutz S, Otten LA, Ceredig R, Acha-Orbea H, Finke D. Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity. 2007. 26:643–654.

29. Chappaz S, Finke D. The IL-7 signaling pathway regulates lymph node development independent of peripheral lymphocytes. J Immunol. 2010. 184:3562–3569.

30. Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011. 12:21–27.

31. Park JH, Adoro S, Lucas PJ, Sarafova SD, Alag AS, Doan LL, Erman B, Liu X, Ellmeier W, Bosselut R, Feigenbaum L, Singer A. 'Coreceptor tuning': cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat Immunol. 2007. 8:1049–1059.

32. Park JH, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, Singer A. Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity. 2004. 21:289–302.

33. Guimond M, Fry TJ, Mackall CL. Cytokine signals in T-cell homeostasis. J Immunother. 2005. 28:289–294.

34. Namen AE, Lupton S, Hjerrild K, Wignall J, Mochizuki DY, Schmierer A, Mosley B, March CJ, Urdal D, Gillis S. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature. 1988. 333:571–573.

35. Goodwin RG, Lupton S, Schmierer A, Hjerrild KJ, Jerzy R, Clevenger W, Gillis S, Cosman D, Namen AE. Human interleukin 7: molecular cloning and growth factor activity on human and murine B-lineage cells. Proc Natl Acad Sci U S A. 1989. 86:302–306.

36. Link A, Vogt TK, Favre S, Britschgi MR, Acha-Orbea H, Hinz B, Cyster JG, Luther SA. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol. 2007. 8:1255–1265.

37. Watanabe M, Ueno Y, Yajima T, Iwao Y, Tsuchiya M, Ishikawa H, Aiso S, Hibi T, Ishii H. Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes. J Clin Invest. 1995. 95:2945–2953.

38. Golden-Mason L, Kelly AM, Traynor O, McEntee G, Kelly J, Hegarty JE, O'Farrelly C. Expression of interleukin 7 (IL-7) mRNA and protein in the normal adult human liver: implications for extrathymic T cell development. Cytokine. 2001. 14:143–151.

39. Heufler C, Topar G, Grasseger A, Stanzl U, Koch F, Romani N, Namen AE, Schuler G. Interleukin 7 is produced by murine and human keratinocytes. J Exp Med. 1993. 178:1109–1114.

40. Matsue H, Bergstresser PR, Takashima A. Keratinocyte-derived IL-7 serves as a growth factor for dendritic epidermal T cells in mice. J Immunol. 1993. 151:6012–6019.

41. Cheng Y, Yata A, Klein C, Cho JH, Deguchi M, Hsueh AJ. Oocyte-Expressed Interleukin 7 Suppresses Granulosa Cell Apoptosis and Promotes Oocyte Maturation in Rats. Biol Reprod. 2010. [Epub ahead of print].

42. Moors M, Vudattu NK, Abel J, Krämer U, Rane L, Ulfig N, Ceccatelli S, Seyfert-Margolies V, Fritsche E, Maeurer MJ. Interleukin-7 (IL-7) and IL-7 splice variants affect differentiation of human neural progenitor cells. Genes Immun. 2010. 11:11–20.

43. Di Carlo E, D'Antuono T, Pompa P, Giuliani R, Rosini S, Stuppia L, Musiani P, Sorrentino C. The lack of epithelial interleukin-7 and BAFF/BLyS gene expression in prostate cancer as a possible mechanism of tumor escape from immunosurveillance. Clin Cancer Res. 2009. 15:2979–2987.

44. Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim SY, Na R, Hennighausen L, Kurtulus S, Erman B, Matzinger P, Merchant MS, Mackall CL. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol. 2009. 10:149–157.

45. Banwell CM, Partington KM, Jenkinson EJ, Anderson G. Studies on the role of IL-7 presentation by mesenchymal fibroblasts during early thymocyte development. Eur J Immunol. 2000. 30:2125–2129.

46. Lai L, Goldschneider I. Cutting edge: Identification of a hybrid cytokine consisting of IL-7 and the beta-chain of the hepatocyte growth factor/scatter factor. J Immunol. 2001. 167:3550–3554.

47. Fry TJ, Mackall CL. The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol. 2005. 174:6571–6576.

48. Muthukumar A, Wozniakowski A, Gauduin MC, Paiardini M, McClure HM, Johnson RP, Silvestri G, Sodora DL. Elevated interleukin-7 levels not sufficient to maintain T-cell homeostasis during simian immunodeficiency virus-induced disease progression. Blood. 2004. 103:973–979.

49. Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, Herndier BG, Andersson J, McCune JM. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med. 2001. 7:73–79.

50. Sawa Y, Arima Y, Ogura H, Kitabayashi C, Jiang JJ, Fukushima T, Kamimura D, Hirano T, Murakami M. Hepatic interleukin-7 expression regulates T cell responses. Immunity. 2009. 30:447–457.

51. Alves NL, Richard-Le Goff O, Huntington ND, Sousa AP, Ribeiro VS, Bordack A, Vives FL, Peduto L, Chidgey A, Cumano A, Boyd R, Eberl G, Di Santo JP. Characterization of the thymic IL-7 niche in vivo. Proc Natl Acad Sci U S A. 2009. 106:1512–1517.

52. Repass JF, Laurent MN, Carter C, Reizis B, Bedford MT, Cardenas K, Narang P, Coles M, Richie ER. IL7-hCD25 and IL7-Cre BAC transgenic mouse lines: new tools for analysis of IL-7 expressing cells. Genesis. 2009. 47:281–287.

53. Mazzucchelli RI, Warming S, Lawrence SM, Ishii M, Abshari M, Washington AV, Feigenbaum L, Warner AC, Sims DJ, Li WQ, Hixon JA, Gray DH, Rich BE, Morrow M, Anver MR, Cherry J, Naf D, Sternberg LR, McVicar DW, Farr AG, Germain RN, Rogers K, Jenkins NA, Copeland NG, Durum SK. Visualization and identification of IL-7 producing cells in reporter mice. PLoS One. 2009. 4:e7637.

54. Shalapour S, Deiser K, Sercan O, Tuckermann J, Minnich K, Willimsky G, Blankenstein T, Hämmerling GJ, Arnold B, Schüler T. Commensal microflora and interferon-gamma promote steady-state interleukin-7 production in vivo. Eur J Immunol. 2010. 40:2391–2400.

55. Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet. 1999. 21:70–71.

56. Srinivas S, Watanabe T, Lin CS, William CM, Tanabe Y, Jessell TM, Costantini F. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol. 2001. 1:4.

57. Zamisch M, Moore-Scott B, Su DM, Lucas PJ, Manley N, Richie ER. Ontogeny and regulation of IL-7-expressing thymic epithelial cells. J Immunol. 2005. 174:60–67.

58. Szymczak AL, Workman CJ, Wang Y, Vignali KM, Dilioglou S, Vanin EF, Vignali DA. Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector. Nat Biotechnol. 2004. 22:589–594.

59. Fry TJ, Mackall CL. Interleukin-7: master regulator of peripheral T-cell homeostasis? Trends Immunol. 2001. 22:564–571.

60. Alves NL, Huntington ND, Mention JJ, Richard-Le Goff O, Di Santo JP. Cutting Edge: a thymocyte-thymic epithelial cell cross-talk dynamically regulates intrathymic IL-7 expression in vivo. J Immunol. 2010. 184:5949–5953.

61. Chappaz S, Flueck L, Farr AG, Rolink AG, Finke D. Increased TSLP availability restores T- and B-cell compartments in adult IL-7 deficient mice. Blood. 2007. 110:3862–3870.

62. Mazo IB, Honczarenko M, Leung H, Cavanagh LL, Bonasio R, Weninger W, Engelke K, Xia L, McEver RP, Koni PA, Silberstein LE, von Andrian UH. Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity. 2005. 22:259–270.

63. Oshima S, Nakamura T, Namiki S, Okada E, Tsuchiya K, Okamoto R, Yamazaki M, Yokota T, Aida M, Yamaguchi Y, Kanai T, Handa H, Watanabe M. Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells. Mol Cell Biol. 2004. 24:6298–6310.