Clinical Rheumatology

, Volume 32, Issue 12, pp 1703–1709 | Cite as

Perspectives of the relationship between IL-7 and autoimmune diseases

  • Xiao-Song Wang
  • Bao-Zhu Li
  • Lin-Feng Hu
  • Peng-Fei Wen
  • Min Zhang
  • Hai-Feng Pan
  • Dong-Qing Ye
Review Article


Interleukin (IL)-7 is one of the IL-2 family cytokines comprised of IL-2, IL-4, IL-7, IL-9, IL-15, as well as IL-21. IL-7 is mainly secreted by stroma cells in primary lymphoid tissues, playing an essential role in the program of T cell development. Recently, studies have revealed that physiological function exerted by immunocytes can be influenced by aberrant IL-7 signaling, which is common in abnormal autoimmunity regulation. There is also increasing evidence that IL-7 is involved in several autoimmune diseases, such as rheumatoid arthritis, type I diabetes, multiple sclerosis and systemic lupus erythematosus, etc. Targeting components in IL-7 signaling pathways may have potential significance for treating numerous autoimmune diseases. In this review, we therefore summarize our current understandings regarding the relationship between IL-7 and autoimmune diseases so as to render more valuable information on this kind of research.


Autoimmune diseases Interleukin-7 Interleukin-7 receptor MS RA SLE T1D 



This work was partly supported by grants from the National Natural Science Foundation of China (30830089), Specialized Research Fund for the Doctoral Program of Higher Education of China (20113420120008), and the Anhui Provincial Natural Science Foundation (11040606M183).




  1. 1.
    Bikker A, Hack CE, Lafeber FP, van Roon JA (2012) Interleukin-7: a key mediator in T cell-driven autoimmunity, inflammation, and tissue destruction. Curr Pharm Des 18(16):2347–2356PubMedCrossRefGoogle Scholar
  2. 2.
    van Roon JA, Verweij MC, Wijk MW et al (2005) Increased intraarticular interleukin-7 in rheumatoid arthritis patients stimulates cell contact-dependent activation of CD4(+) T cells and macrophages. Arthritis Rheum 52(6):1700–1710PubMedCrossRefGoogle Scholar
  3. 3.
    Harrison C (2012) Autoimmune disease: targeting IL-7 reverses type 1 diabetes. Nat Rev Drug Discov 11(8):599PubMedCrossRefGoogle Scholar
  4. 4.
    Liu X, Leung S, Wang C et al (2010) Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. Nat Med 16(2):191–197PubMedCrossRefGoogle Scholar
  5. 5.
    Gregory SG, Schmidt S, Seth P et al (2007) Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 39(9):1083–1091PubMedCrossRefGoogle Scholar
  6. 6.
    Badot V, Luijten RK, van Roon JA et al (2013) Serum soluble interleukin 7 receptor is strongly associated with lupus nephritis in patients with systemic lupus erythematosus. Ann Rheum Dis 72(3):453–456PubMedCrossRefGoogle Scholar
  7. 7.
    Lundström W, Highfill S, Walsh ST et al (2013) Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity. Proc Natl Acad Sci U S A 110(19):E1761–E1770PubMedCrossRefGoogle Scholar
  8. 8.
    Pillai M, Torok-Storb B, Iwata M (2004) Expression and function of IL-7 receptors in marrow stromal cells. Leuk Lymphoma 45(12):2403–2408PubMedCrossRefGoogle Scholar
  9. 9.
    McElroy CA, Dohm JA, Walsh ST (2009) Structural and biophysical studies of the human IL-7/IL-7Ralpha complex. Structure 17(1):54–65PubMedCrossRefGoogle Scholar
  10. 10.
    Ceredig R, Rolink AG (2012) The key role of IL-7 in lymphopoiesis. Semin Immunol 24(3):159–164PubMedCrossRefGoogle Scholar
  11. 11.
    Hong C, Luckey MA, Park J-H (2012) Intrathymic IL-7: the where, when, and why of IL-7 signaling during T cell development. Semin Immunol 24(3):151–158PubMedCrossRefGoogle Scholar
  12. 12.
    Jiang Q, Huang J, Li WQ et al (2007) Role of the intracellular domain of IL-7 receptor in T cell development. J Immunol 178(1):228–234PubMedGoogle Scholar
  13. 13.
    Mazzucchelli R, Durum SK (2007) Interleukin-7 receptor expression: intelligent design. Nat Rev Immunol 7(2):144–154PubMedCrossRefGoogle Scholar
  14. 14.
    Rose T, Pillet AH, Lavergne V et al (2010) Interleukin-7 compartmentalizes its receptor signaling complex to initiate CD4 T lymphocyte response. J Biol Chem 285(20):14898–14908PubMedCrossRefGoogle Scholar
  15. 15.
    Benbernou N, Muegge K, Durum SK (2000) Interleukin (IL)-7 induces rapid activation of Pyk2, which is bound to Janus kinase 1 and IL-7Ralpha. J Biol Chem 275(10):7060–7065PubMedCrossRefGoogle Scholar
  16. 16.
    Quintas-Cardama A, Verstovsek S (2013) Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin Cancer Res 19(8):1933–1940PubMedCrossRefGoogle Scholar
  17. 17.
    Palmer MJ, Mahajan VS, Trajman LC et al (2008) Interleukin-7 receptor signaling network: an integrated systems perspective. Cell Mol Immunol 5(2):79–89PubMedCrossRefGoogle Scholar
  18. 18.
    Jiang Q, Li WQ, Aiello FB et al (2005) Cell biology of IL-7, a key lymphotrophin. Cytokine Growth Factor Rev 16(4–5):513–533PubMedCrossRefGoogle Scholar
  19. 19.
    Ivashkiv LB, Hu X (2004) Signaling by STATs. Arthritis Res Ther 6(4):159–168PubMedCrossRefGoogle Scholar
  20. 20.
    Corfe SA, Paige CJ (2012) The many roles of IL-7 in B cell development; mediator of survival, proliferation and differentiation. Semin Immunol 24(3):198–208PubMedCrossRefGoogle Scholar
  21. 21.
    Smyth CM, Ginn SL, Deakin CT et al (2007) Limiting {gamma}c expression differentially affects signaling via the interleukin IL-7 and IL-15 receptors. Blood 110(1):91–98PubMedCrossRefGoogle Scholar
  22. 22.
    Carrette F, Surh CD (2012) IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis. Semin Immunol 24(3):209–217PubMedCrossRefGoogle Scholar
  23. 23.
    Boyman O, Ramsey C, Kim DM, Sprent J et al (2008) IL-7/anti-IL-7 mAb complexes restore T cell development and induce homeostatic T Cell expansion without lymphopenia. J Immunol 180(11):7265–7275PubMedGoogle Scholar
  24. 24.
    El-Kassar N, Flomerfelt FA, Choudhury B et al (2012) High levels of IL-7 cause dysregulation of thymocyte development. Int Immunol 24(10):661–671PubMedCrossRefGoogle Scholar
  25. 25.
    Milne CD, Paige CJ (2006) IL-7: a key regulator of B lymphopoiesis. Semin Immunol 18(1):20–30PubMedCrossRefGoogle Scholar
  26. 26.
    Akashi K, Kondo M, von Freeden-Jeffry U et al (1997) Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 89(7):1033–1041PubMedCrossRefGoogle Scholar
  27. 27.
    Malin S, McManus S, Busslinger M (2010) STAT5 in B cell development and leukemia. Curr Opin Immunol 22(2):168–176PubMedCrossRefGoogle Scholar
  28. 28.
    Holm AM, Aukrust P, Damås JK, Müller F et al (2005) Abnormal interleukin-7 function in common variable immunodeficiency. Blood 105(7):2887–2890PubMedCrossRefGoogle Scholar
  29. 29.
    Lundstrom W, Fewkes NM, Mackall CL (2012) IL-7 in human health and disease. Semin Immunol 24(3):218–224PubMedCrossRefGoogle Scholar
  30. 30.
    Todd JA, Walker NM, Cooper JD et al (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39(7):857–864PubMedCrossRefGoogle Scholar
  31. 31.
    Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423(6937):356–361PubMedCrossRefGoogle Scholar
  32. 32.
    Bartok B, Firestein GS (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233(1):233–255PubMedCrossRefGoogle Scholar
  33. 33.
    Fry TJ, Mackall CL (2002) Interleukin-7: from bench to clinic. Blood 99(11):3892–3904PubMedCrossRefGoogle Scholar
  34. 34.
    van Amelsfort JM, van Roon JA, Noordegraaf M et al (2007) Proinflammatory mediator-induced reversal of CD4+, CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum 56(3):732–742PubMedCrossRefGoogle Scholar
  35. 35.
    Churchman SM, Ponchel F (2008) Interleukin-7 in rheumatoid arthritis. Rheumatology (Oxford) 47(6):753–759CrossRefGoogle Scholar
  36. 36.
    Natsumeda M, Nishiya K, Ota Z (1993) Stimulation by interleukin-7 of mononuclear cells in peripheral blood, synovial fluid and synovial tissue from patients with rheumatoid arthritis. Acta Med Okayama 47(6):391–397PubMedGoogle Scholar
  37. 37.
    Sawa S, Kamimura D, Jin GH et al (2006) Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells. J Exp Med 203(6):1459–1470PubMedCrossRefGoogle Scholar
  38. 38.
    Harada S, Yamamura M, Okamoto H et al (1999) Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum 42(7):1508–1516PubMedCrossRefGoogle Scholar
  39. 39.
    van Roon JA, Glaudemans KA, Bijlsma JW et al (2003) Interleukin 7 stimulates tumour necrosis factor alpha and Th1 cytokine production in joints of patients with rheumatoid arthritis. Ann Rheum Dis 62(2):113–119PubMedCrossRefGoogle Scholar
  40. 40.
    Pickens SR, Chamberlain ND, Volin MV et al (2011) Characterization of interleukin-7 and interleukin-7 receptor in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 63(10):2884–2893PubMedCrossRefGoogle Scholar
  41. 41.
    Rekha P, Conaghan PG, Paul E et al (2012) Progression to rheumatoid arthritis in early inflammatory arthritis is associated with low IL-7 serum levels. Ann Rheum Dis 72(6):1032–1036Google Scholar
  42. 42.
    Makino T, Fukushima S, Wakasugi S et al (2009) Decreased serum IL-7 levels in patients with systemic sclerosis. Clin Exp Rheumatol 27(3 Suppl 54):68–69PubMedGoogle Scholar
  43. 43.
    Kader HA, Tchernev VT, Satyaraj E et al (2005) Protein microarray analysis of disease activity in pediatric inflammatory bowel disease demonstrates elevated serum PLGF, IL-7, TGF-beta1, and IL-12p40 levels in Crohn's disease and ulcerative colitis patients in remission versus active disease. Am J Gastroenterol 100(2):414–423PubMedCrossRefGoogle Scholar
  44. 44.
    Lee LF, Logronio K, Tu GH et al (2012) Anti-IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function. Proc Natl Acad Sci U S A 109(31):12674–12679PubMedCrossRefGoogle Scholar
  45. 45.
    Maahs DM, West NA, Lawrence JM et al (2010) Epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am 39(3):481–497PubMedCrossRefGoogle Scholar
  46. 46.
    Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447–485PubMedCrossRefGoogle Scholar
  47. 47.
    Bluestone JA, Herold K, Eisenbarth G (2010) Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464(7293):1293–1300PubMedCrossRefGoogle Scholar
  48. 48.
    Lee LF, Axtell R, Tu GH et al (2011) IL-7 promotes T(H)1 development and serum IL-7 predicts clinical response to interferon-β in multiple sclerosis. Sci Transl Med 3(93):93ra68PubMedCrossRefGoogle Scholar
  49. 49.
    Penaranda C, Kuswanto W, Hofmann J et al (2012) IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells. Proc Natl Acad Sci U S A 109(31):12668–12673PubMedCrossRefGoogle Scholar
  50. 50.
    Keir ME, Liang SC, Guleria I et al (2006) Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 203(4):883–895PubMedCrossRefGoogle Scholar
  51. 51.
    Hafler DA (2004) Multiple sclerosis. J Clin Invest 113(6):788–794PubMedGoogle Scholar
  52. 52.
    McFarlin DE, McFarland HF (1982) Multiple sclerosis (first of two parts). N Engl J Med 307(19):1183–1188PubMedCrossRefGoogle Scholar
  53. 53.
    McFarlin DE, McFarland HF (1982) Multiple sclerosis (second of two parts). N Engl J Med 307(20):1246–1251PubMedCrossRefGoogle Scholar
  54. 54.
    Fernald GH, Yeh RF, Hauser SL et al (2005) Mapping gene activity in complex disorders: Integration of expression and genomic scans for multiple sclerosis. J Neuroimmunol 167(1–2):157–169PubMedCrossRefGoogle Scholar
  55. 55.
    Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747PubMedCrossRefGoogle Scholar
  56. 56.
    Kreft KL, Verbraak E, Wierenga-Wolf AF et al (2012) Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients. Genes Immun 13(7):587–592PubMedCrossRefGoogle Scholar
  57. 57.
    Walline CC, Kanakasabai S, Bright JJ (2011) IL-7Rα confers susceptibility to experimental autoimmune encephalomyelitis. Genes Immun 12(1):1–14PubMedCrossRefGoogle Scholar
  58. 58.
    Lock C, Hermans G, Pedotti R et al (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8(5):500–508PubMedCrossRefGoogle Scholar
  59. 59.
    McGeachy MJ, Chen Y, Tato CM et al (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10(3):314–324PubMedCrossRefGoogle Scholar
  60. 60.
    Chen Y, Langrish CL, McKenzie B et al (2006) Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 116(5):1317–1326PubMedCrossRefGoogle Scholar
  61. 61.
    Tiffin N, Adeyemo A, Okpechi I (2013) A diverse array of genetic factors contribute to the pathogenesis of systemic lupus erythematosus. Orphanet J Rare Dis 8(1):2PubMedCrossRefGoogle Scholar
  62. 62.
    Tsokos GC (2011) Systemic lupus erythematosus. N Engl J Med 365(22):2110–2121PubMedCrossRefGoogle Scholar
  63. 63.
    Pons-Estel GJ, Alarcón GS, Scofield L et al (2010) Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 39(4):257–268PubMedCrossRefGoogle Scholar
  64. 64.
    Pan HF, Ye DQ, Li XP (2008) Type 17 T-helper cells might be a promising therapeutic target for systemic lupus erythematosus. Nat Clin Pract Rheumatol 4(7):352–353PubMedGoogle Scholar
  65. 65.
    Ohl K, Tenbrock K (2011) Inflammatory cytokines in systemic lupus erythematosus. J Biomed Biotechnol 2011:432595PubMedCrossRefGoogle Scholar
  66. 66.
    Ambrosi A, Espinosa A, Wahren-Herlenius M (2012) IL-17: a new actor in IFN-driven systemic autoimmune diseases. Eur J Immunol 42(9):2274–2284PubMedCrossRefGoogle Scholar
  67. 67.
    Yang Y, Xiao X, Li F et al (2012) Increased IL-7 expression in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 53(2):1012–1017PubMedCrossRefGoogle Scholar
  68. 68.
    Bikker A, Moret FM, Kruize AA et al (2012) IL-7 drives Th1 and Th17 cytokine production in patients with primary SS despite an increase in CD4 T cells lacking the IL-7Rα. Rheumatology (Oxford) 51(6):996–1005CrossRefGoogle Scholar
  69. 69.
    Ben-David H, Sharabi A, Parameswaran R et al (2009) A tolerogenic peptide down-regulates mature B cells in bone marrow of lupus-afflicted mice by inhibition of interleukin-7, leading to apoptosis. Immunology 128(2):245–252PubMedCrossRefGoogle Scholar

Copyright information

© Clinical Rheumatology 2013

Authors and Affiliations

  • Xiao-Song Wang
    • 1
  • Bao-Zhu Li
    • 1
  • Lin-Feng Hu
    • 1
  • Peng-Fei Wen
    • 1
  • Min Zhang
    • 1
  • Hai-Feng Pan
    • 1
  • Dong-Qing Ye
    • 1
  1. 1.Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiPeople’s Republic of China

Personalised recommendations