Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Harnessing the biology of IL-7 for therapeutic application

Nature Reviews Immunology volume 11, pages 330–342 (2011)Cite this article

Subjects

Key Points

  • Interleukin-7 (IL-7) is required for T cell development in mice and humans and is produced by stromal tissues rather than activated lymphocytes. Under normal conditions, IL-7 is a limiting resource for T cells, but it accumulates during lymphopenic conditions. IL-7 signals through a heterodimeric receptor consisting of the IL-7 receptor α-chain (IL-7Rα) and the common cytokine receptor γ-chain (γc).

  • IL-7 is not required for human B cell development in fetal life, but it affects early B cell progenitors and contributes to B cell development under normal conditions.

  • IL-7 has also been recently demonstrated to regulate lymphoid tissue inducer (LTi) cells, which induce the development of secondary lymphoid organs and can induce tertiary lymphoid tissue postnatally in settings of chronic inflammation.

  • In animals, IL-7 therapy enhances the effectiveness of adoptive immunotherapy for cancer, enhances vaccine responses and enhances viral clearance in the setting of acute and chronic infections.

  • In mature T cells, IL-7Rα is most highly expressed on recent thymic emigrants, maintained on naive T cells, downregulated upon T cell activation, and re-expressed on memory T cell subsets. As a result, treatment with recombinant human IL-7 (rhIL-7) preferentially expands recent thymic emigrants and naive T cells, as well as central memory T cells, but largely spares senescent T cells and regulatory T cells. This results in increased repertoire diversity following rhIL-7 therapy in humans.

  • Clinical results with rhIL-7 thus far have shown it to be well tolerated with dose-dependent increases in T cell numbers that persist long after the cytokine is cleared. Based on the pharmacological and biological properties demonstrated thus far, IL-7 is particularly well-suited as a therapy for conditions associated with lymphocyte immunodeficiency.

  • Multiple trials are ongoing or planned in HIV infection, other chronic infections (including hepatitis B and C), cancer (including as an adjuvant to immune-based therapies), post-haematopoietic stem cell transplantation and ageing.

Abstract

Interleukin-7 (IL-7) is required for T cell development and for maintaining and restoring homeostasis of mature T cells. IL-7 is a limiting resource under normal conditions, but it accumulates during lymphopaenia, leading to increased T cell proliferation. The administration of recombinant human IL-7 to normal or lymphopenic mice, non-human primates and humans results in widespread T cell proliferation, increased T cell numbers, modulation of peripheral T cell subsets and increased T cell receptor repertoire diversity. These effects raise the prospect that IL-7 could mediate therapeutic benefits in several clinical settings. This Review summarizes the biology of IL-7 and the results of its clinical use that are available so far to provide a perspective on the opportunities for clinical application of this cytokine.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: IL-7-mediated signalling pathways.
Figure 2: IL-7R expression by lymphocytes.
Figure 3: Distinctions between a prototypical activation cytokine (IL-2) and a prototypical homeostatic cytokine (IL-7).
Figure 4: Recombinant human IL-7 diversifies the TCR repertoire by preferential expansion of naive T cell populations and recent thymic emigrants.

References

  1. Guimond, M. et al. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nature Immunol. 10, 149–157 (2009). The first definitive evidence that the increased levels of IL-7 during lymphopaenia are the result of decreased consumption rather than increased production. This study also identifies IL-7-mediated signalling on DCs as a modulator of T cell homeostasis.

    Article  CAS  Google Scholar 

  2. Pellegrini, M. et al. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nature Med. 15, 528–536 (2009). This study provides mechanistic insight into the vaccine adjuvant effect of IL-7 and increases the known targets of IL-7-mediated signalling to include negative regulators of the T cell response such as CBL-B and SMURF2.

    Article  CAS  PubMed  Google Scholar 

  3. Park, J. H. et al. Suppression of IL7Rα transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 21, 289–302 (2004). This study established IL-7 as a limiting resource for T cells.

    Article  CAS  PubMed  Google Scholar 

  4. Fry, T. J. et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 101, 2294–2299 (2003). The first demonstration that the effects of in vivo IL-7 administration extend to non-human primates. This study also showed that IL-7-mediated signalling downregulates expression of IL-7Rα.

    Article  CAS  PubMed  Google Scholar 

  5. Khaled, A. R. & Durum, S. K. Death and Baxes: mechanisms of lymphotrophic cytokines. Immunol. Rev. 193, 48–57 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Jiang, Q. et al. Cell biology of IL-7, a key lymphotrophin. Cytokine Growth Factor Rev. 16, 513–533 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Puel, A., Ziegler, S. F., Buckley, R. H. & Leonard, W. J. Defective IL7R expression in T−B+NK+ severe combined immunodeficiency. Nature Genet. 20, 394–397 (1998). The first description in humans of SCID due to deficiency of IL-7Rα signalling. This study identified important differences in lymphocyte development between mice and humans.

    Article  CAS  PubMed  Google Scholar 

  8. Cunningham-Rundles, C. & Ponda, P. P. Molecular defects in T- and B-cell primary immunodeficiency diseases. Nature Rev. Immunol. 5, 880–892 (2005).

    Article  CAS  Google Scholar 

  9. Mazzucchelli, R. & Durum, S. K. Interleukin-7 receptor expression: intelligent design. Nature Rev. Immunol. 7, 144–154 (2007). A definitive review of the role of IL-7Rα in T cell development.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Maraskovsky, E. et al. Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1−/− mice. Cell 89, 1011–1019 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Pellegrini, M. et al. Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice. J. Exp. Med. 200, 1189–1195 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Khaled, A. R. et al. Bax deficiency partially corrects interleukin-7 receptor-α deficiency. Immunity 17, 561–573 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Al-Shami, A. et al. A role for thymic stromal lymphopoietin in CD4+ T cell development. J. Exp. Med. 200, 159–168 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vang, K. B. et al. IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J. Immunol. 181, 3285–3290 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Mazzucchelli, R. et al. Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP. Blood 112, 3283–3292 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bayer, A. L., Lee, J. Y., de la Barrera, A., Surh, C. D. & Malek, T. R. A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells. J. Immunol. 181, 225–234 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Herzog, S., Reth, M. & Jumaa, H. Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling. Nature Rev. Immunol. 9, 195–205 (2009).

    Article  CAS  Google Scholar 

  19. Parrish, Y. K. et al. IL-7 dependence in human B lymphopoiesis increases during progression of ontogeny from cord blood to bone marrow. J. Immunol. 182, 4255–4266 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Shriner, A. K., Liu, H., Sun, G., Guimond, M. & Alugupalli, K. R. IL-7-dependent B lymphocytes are essential for the anti-polysaccharide response and protective immunity to Streptococcus pneumoniae. J. Immunol. 185, 525–531 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Kikuchi, K., Lai, A. Y., Hsu, C. L. & Kondo, M. IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF. J. Exp. Med. 201, 1197–1203 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Johnson, K. et al. Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling. Immunity 28, 335–345 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Corcoran, A. E., Riddell, A., Krooshoop, D. & Venkitaraman, A. R. Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor. Nature 391, 904–907 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Bertolino, E. et al. Regulation of interleukin 7-dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5. Nature Immunol. 6, 836–843 (2005).

    Article  CAS  Google Scholar 

  25. Malin, S. et al. Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development. Nature Immunol. 11, 171–179 (2010).

    Article  CAS  Google Scholar 

  26. Brown, V. I. et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc. Natl Acad. Sci. USA 100, 15113–15118 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yoda, A. et al. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 107, 252–257 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Liu, Y. J. et al. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu. Rev. Immunol. 25, 193–219 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Vogt, T. K., Link, A., Perrin, J., Finke, D. & Luther, S. A. Novel function for interleukin-7 in dendritic cell development. Blood 113, 3961–3968 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Vosshenrich, C. A. et al. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nature Immunol. 7, 1217–1224 (2006).

    Article  CAS  Google Scholar 

  31. Ribeiro, V. S. et al. Cutting edge: Thymic NK cells develop independently from T cell precursors. J. Immunol. 185, 4993–4997 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Eberl, G. et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nature Immunol. 5, 64–73 (2004).

    Article  CAS  Google Scholar 

  33. Luther, S. A., Ansel, K. M. & Cyster, J. G. Overlapping roles of CXCL13, interleukin 7 receptor-α, and CCR7 ligands in lymph node development. J. Exp. Med. 197, 1191–1198 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nishikawa, S., Honda, K., Vieira, P. & Yoshida, H. Organogenesis of peripheral lymphoid organs. Immunol Rev. 195, 72–80 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Meier, D. et al. Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity 26, 643–654 (2007). This study identifies the importance of IL-7 for the homeostasis of LTi cells and, therefore, the ability of IL-7 to regulate SLO development.

    Article  CAS  PubMed  Google Scholar 

  36. Schmutz, S. et al. Cutting edge: IL-7 regulates the peripheral pool of adult RORγ+ lymphoid tissue inducer cells. J. Immunol. 183, 2217–2221 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Tsuji, M. et al. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29, 261–271 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nature Med. 10, 927–934 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nature Rev. Immunol. 6, 205–217 (2006).

    Article  CAS  Google Scholar 

  41. Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Cupedo, T. et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+CD127+ natural killer-like cells. Nature Immunol. 10, 66–74 (2009).

    Article  CAS  Google Scholar 

  43. Vonarbourg, C. et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cella, M., Otero, K. & Colonna, M. Expansion of human NK-22 cells with IL-7, IL-2, and IL-1β reveals intrinsic functional plasticity. Proc. Natl Acad. Sci. USA 107, 10961–10966 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nature Immunol. 1, 426–432 (2000). The first demonstration that IL-7 is required for the homeostatic proliferation of CD8+ T cells during lymphopenic conditions.

    Article  CAS  Google Scholar 

  46. Takada, K. & Jameson, S. C. Naive T cell homeostasis: from awareness of space to a sense of place. Nature Rev. Immunol. 9, 823–832 (2009).

    Article  CAS  Google Scholar 

  47. Ouyang, W., Beckett, O., Flavell, R. A. & Li, M. O. An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 30, 358–371 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Grenningloh, R. et al. Ets-1 maintains IL-7 receptor expression in peripheral T cells. J. Immunol. 186, 969–976 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Matsue, H., Bergstresser, P. R. & Takashima, A. Keratinocyte-derived IL-7 serves as a growth factor for dendritic epidermal T cells in mice. J. Immunol. 151, 6012–6019 (1993).

    CAS  PubMed  Google Scholar 

  50. Thang, P. H. et al. The role of IL-1β in reduced IL-7 production by stromal and epithelial cells: a model for impaired T-cell numbers in the gut during HIV-1 infection. J. Intern. Med. 268, 181–193 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Watanabe, M. et al. Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes. J. Clin. Invest. 95, 2945–2953 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sawa, Y. et al. Hepatic interleukin-7 expression regulates T cell responses. Immunity 30, 447–457 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Kaech, S. M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunol. 4, 1191–1198 (2003).

    Article  CAS  Google Scholar 

  54. Tan, J. T. et al. 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. 195, 1523–1532 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kieper, W. C. et al. Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J. Exp. Med. 195, 1533–1539 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dardalhon, V. et al. IL-7 differentially regulates cell cycle progression and HIV-1-based vector infection in neonatal and adult CD4+ T cells. Proc. Natl Acad. Sci. USA 98, 9277–9282 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Swainson, L. et al. IL-7-induced proliferation of recent thymic emigrants requires activation of the PI3K pathway. Blood 109, 1034–1042 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Ernst, B., Lee, D. S., Chang, J. M., Sprent, J. & Surh, C. D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Goldrath, A. W. & Bevan, M. J. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183–190 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Paiardini, M. et al. Loss of CD127 expression defines an expansion of effector CD8+ T cells in HIV-infected individuals. J. Immunol. 174, 2900–2909 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ TReg cells. J. Exp. Med. 203, 1701–1711 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Simonetta, F. et al. Increased CD127 expression on activated FOXP3+CD4+ regulatory T cells. Eur. J. Immunol. 40, 2528–2538 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Bolotin, E., Annett, G., Parkman, R. & Weinberg, K. Serum levels of IL-7 in bone marrow transplant recipients: relationship to clinical characteristics and lymphocyte count. Bone Marrow Transplant. 23, 783–788 (1999). The first observation that serum IL-7 levels are increased during lymphopaenia after bone marrow transplantation. These findings were identified as a general feature of lymphopaenia with the discovery of increased IL-7 levels in other clinical conditions associated with T cell deficiency in references 65 and 66.

    Article  CAS  PubMed  Google Scholar 

  65. Fry, T. J. et al. A potential role for interleukin-7 in T-cell homeostasis. Blood 97, 2983–2990 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Napolitano, L. A. et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nature Med. 7, 73–79 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Spivak, J. L. Erythropoietin: from bench to bedside. Trans. Am. Clin. Climatol. Assoc. 102, 232–242 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kuter, D. J. & Begley, C. G. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood 100, 3457–3469 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Takatani, H. et al. Levels of recombinant human granulocyte colony-stimulating factor in serum are inversely correlated with circulating neutrophil counts. Antimicrob. Agents Chemother. 40, 988–991 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hakim, F. T. et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J. Clin. Invest. 115, 930–939 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mackall, C. L. et al. Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 89, 3700–3707 (1997).

    CAS  PubMed  Google Scholar 

  72. Komschlies, K. L., Grzegorzewski, K. J. & Wiltrout, R. H. Diverse immunological and hematological effects of interleukin 7: implications for clinical application. J. Leukoc. Biol. 58, 623–633 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Storek, J. et al. Interleukin-7 improves CD4 T-cell reconstitution after autologous CD34 cell transplantation in monkeys. Blood 101, 4209–4218 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Fry, T. J., Christensen, B. L., Komschlies, K. L., Gress, R. E. & Mackall, C. L. Interleukin-7 restores immunity in athymic T-cell-depleted hosts. Blood 97, 1525–1533 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Mackall, C. L. et al. IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation. Blood 97, 1491–1497 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Morrissey, P. J. et al. Administration of IL-7 to mice with cyclophosphamide-induced lymphopenia accelerates lymphocyte repopulation. J. Immunol. 146, 1547–1552 (1991).

    CAS  PubMed  Google Scholar 

  77. Bolotin, E., Smogorzewska, M., Smith, S., Widmer, M. & Weinberg, K. Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood 88, 1887–1894 (1996).

    CAS  PubMed  Google Scholar 

  78. Andrew, D. & Aspinall, R. IL-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice. J. Immunol. 166, 1524–1530 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Okamoto, Y., Douek, D. C., McFarland, R. D. & Koup, R. A. Effects of exogenous interleukin-7 on human thymus function. Blood 99, 2851–2858 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Min, D. et al. Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 99, 4592–4600 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Seggewiss, R. et al. Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood 110, 441–449 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Alpdogan, O. et al. Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood 105, 865–873 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Fry, T. J. et al. Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution. Blood 104, 2794–2800 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Melchionda, F. et al. Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool. J. Clin. Invest. 115, 1177–1187 (2005). The first description of the vaccine adjuvant effect of IL-7 and its preferential effects on subdominant antigens.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Frankenberger, B. et al. Influence of CD80, interleukin-2, and interleukin-7 expression in human renal cell carcinoma on the expansion, function, and survival of tumor-specific CTLs. Clin. Cancer Res. 11, 1733–1742 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Wittig, B. et al. Therapeutic vaccination against metastatic carcinoma by expression-modulated and immunomodified autologous tumor cells: a first clinical phase I/II trial. Hum. Gene Ther. 12, 267–278 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Kim, T. S., Chung, S. W. & Hwang, S. Y. Augmentation of antitumor immunity by genetically engineered fibroblast cells to express both B7.1 and interleukin-7. Vaccine 18, 2886–2894 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Colombetti, S., Levy, F. & Chapatte, L. IL-7 adjuvant treatment enhances long-term tumor-antigen-specific CD8+ T-cell responses after immunization with recombinant lentivector. Blood 113, 6629–6637 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Nanjappa, S. G., Walent, J. H., Morre, M. & Suresh, M. Effects of IL-7 on memory CD8 T cell homeostasis are influenced by the timing of therapy in mice. J. Clin. Invest. 118, 1027–1039 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Pellegrini, M. et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144, 601–613 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Nanjappa, S. G., Kim, E. H. & Suresh, M. Immunotherapeutic effects of IL 7 during a chronic viral infection in mice. Blood 23 Mar 2011 (doi:10.1182/blood-2010-12-323154). References 90 and 91 were the first descriptions of the postive effect of IL-7 on T cell-dependent immunity and viral clearance in chronic infection models.

  92. Unsinger, J. et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J. Immunol. 184, 3768–3779 (2010). This study describes the potential for a positive effect of IL-7 therapy in bacterial infection.

    Article  CAS  PubMed  Google Scholar 

  93. Sportes, C. et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J. Exp. Med. 205, 1701–1714 (2008). The first complete description of the immunological effects of rhIL-7 therapy in humans, including the important observation that TCR repertoire diversification occurs, at least in part, through the preferential expansion of RTEs and naive T cell populations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sportes, C. et al. Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy. Clin. Cancer Res. 16, 727–735 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Beq, S. et al. Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques. Blood 114, 816–825 (2009). This study shows that glycosylation of IL-7 can decrease its immunogenicity.

    Article  CAS  PubMed  Google Scholar 

  96. Kitazawa, H. et al. IL-7 activates α4β1 integrin in murine thymocytes. J. Immunol. 159, 2259–2264 (1997).

    CAS  PubMed  Google Scholar 

  97. Rosenberg, S. A. et al. IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J. Immunother. 29, 313–319 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sereti, I. et al. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood 113, 6304–6314 (2009). The first report of IL-7 therapy in HIV-infected individuals. In this study, patients were administered a single dose of IL-7, thereby allowing a definitive description of the length of biological effect of IL-7 in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hakim, F. T. & Gress, R. E. Reconstitution of thymic function after stem cell transplantation in humans. Curr. Opin. Hematol. 9, 490–496 (2002).

    Article  PubMed  Google Scholar 

  100. Chu, Y. W. et al. Exogenous IL-7 increases recent thymic emigrants in peripheral lymphoid tissue without enhanced thymic function. Blood 104, 1110–1119 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Levy, Y. et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J. Clin. Invest. 119, 997–1007 (2009). The first report of the effect of multiple doses of IL-7 in HIV-infected individuals.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Patel, A., Patel, J. & Ikwuagwu, J. A case of progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia. J. Antimicrob. Chemother. 65, 2697–2698 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Abrams, D. et al. Interleukin-2 therapy in patients with HIV infection. N. Engl. J. Med. 361, 1548–1559 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Shamim, Z. et al. Genetic polymorphisms in the genes encoding human interleukin-7 receptor-α: prognostic significance in allogeneic stem cell transplantation. Bone Marrow Transplant. 37, 485–491 (2006). The first description that polymorphisms in the gene encoding IL-7Rα can contribute to human immune-mediated disease.

    Article  CAS  PubMed  Google Scholar 

  105. Dean, R. M. et al. Association of serum interleukin-7 levels with the development of acute graft-versus-host disease. J. Clin. Oncol. 26, 5735–5741 (2008). The first demonstration that serum IL-7 levels are associated with human immune-mediated disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Thiant, S. et al. Plasma levels of IL-7 and IL-15 in the first month after myeloablative BMT are predictive biomarkers of both acute GVHD and relapse. Bone Marrow Transplant. 45, 1546–1552 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Sinha, M. L., Fry, T. J., Fowler, D. H., Miller, G. & Mackall, C. L. Interleukin 7 worsens graft-versus-host disease. Blood 100, 2642–2649 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Fewkes, N. M. & Mackall, C. L. Novel γ-chain cytokines as candidate immune modulators in immune therapies for cancer. Cancer J. 16, 392–398 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kasten, K. R. et al. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through γδ T-cell IL-17 production in a murine model of sepsis. Infect. Immun. 78, 4714–4722 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Uehira, M. et al. The development of dermatitis infiltrated by γδ T cells in IL-7 transgenic mice. Int. Immunol. 5, 1619–1627 (1993).

    Article  CAS  PubMed  Google Scholar 

  111. Lundmark, F. et al. Variation in interleukin 7 receptor α-chain (IL7R) influences risk of multiple sclerosis. Nature Genet. 39, 1108–1113 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Gregory, S. G. et al. Interleukin 7 receptor α-chain (IL7R) shows allelic and functional association with multiple sclerosis. Nature Genet. 39, 1083–1091 (2007). References 111 and 112 provide definitive evidence that IL-7Rα polymorphisms contribute to the genetic risk of autoimmune disease.

    Article  CAS  PubMed  Google Scholar 

  113. Hartgring, S. A., Bijlsma, J. W., Lafeber, F. P. & van Roon, J. A. Interleukin-7 induced immunopathology in arthritis. Ann. Rheum. Dis. 65 (Suppl. 3), 69–74 (2006).

    CAS  Google Scholar 

  114. Hartgring, S. A. et al. Blockade of the interleukin-7 receptor inhibits collagen-induced arthritis and is associated with reduction of T cell activity and proinflammatory mediators. Arthritis Rheum. 62, 2716–2725 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Totsuka, T. et al. IL-7 is essential for the development and the persistence of chronic colitis. J. Immunol. 178, 4737–4748 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Yamazaki, M. et al. Mucosal T cells expressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis. J. Immunol. 171, 1556–1563 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Kirkwood, J. M. et al. Next generation of immunotherapy for melanoma. J. Clin. Oncol. 26, 3445–3455 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Casadevall, N. et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346, 469–475 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nature Rev. Immunol. 10, 664–674 (2010).

    Article  CAS  Google Scholar 

  120. Mebius, R. E. et al. The fetal liver counterpart of adult common lymphoid progenitors gives rise to all lymphoid lineages, CD45+CD4+CD3− cells, as well as macrophages. J. Immunol. 166, 6593–6601 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Boos, M. D., Yokota, Y., Eberl, G. & Kee, B. L. Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J. Exp. Med. 204, 1119–1130 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. GeurtsvanKessel, C. H. et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J. Exp. Med. 206, 2339–2349 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Rangel-Moreno, J., Moyron-Quiroz, J. E., Hartson, L., Kusser, K. & Randall, T. D. Pulmonary expression of CXC chemokine ligand 13, CC chemokine ligand 19, and CC chemokine ligand 21 is essential for local immunity to influenza. Proc. Natl Acad. Sci. USA 104, 10577–10582 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lee, Y. et al. Recruitment and activation of naive T cells in the islets by lymphotoxin-β receptor-dependent tertiary lymphoid structure. Immunity 25, 499–509 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M. & Swartz, M. A. Induction of lymphoid-like stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749–752 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Hughes, T. et al. Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH17 cytokine interleukin-22. Blood 113, 4008–4010 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Luci, C. et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nature Immunol. 10, 75–82 (2009).

    Article  CAS  Google Scholar 

  128. Satoh-Takayama, N. et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958–970 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Piketty, C. et al. Long-term clinical outcome of human immunodeficiency virus-infected patients with discordant immunologic and virologic responses to a protease inhibitor-containing regimen. J. Infect. Dis. 183, 1328–1335 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Engsig, F. N. et al. Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: a cohort study. BMC Infect. Dis. 10, 318 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Gutierrez, F. et al. Patients' characteristics and clinical implications of suboptimal CD4 T-cell gains after 1 year of successful antiretroviral therapy. Curr. HIV Res. 6, 100–107 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Mackall, C. et al. Background to hematopoietic cell transplantation, including post transplant immune recovery. Bone Marrow Transplant. 44, 457–462 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank S. Durum for his critical review of the manuscript and his helpful discussions. This work was supported by the Intramural Research Program of the National Institutes of Health, USA.

Author information

Authors and Affiliations

  1. Immunology Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

    Crystal L. Mackall

  2. Blood and Marrow Transplant Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

    Terry J. Fry

  3. Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

    Ronald E. Gress

Authors
  1. Crystal L. Mackall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Terry J. Fry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald E. Gress
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Crystal L. Mackall.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

Janus kinase–signal transducer and activator of transcription pathway

(JAK–STAT pathway). An evolutionarily conserved signalling pathway that is associated with type I and type II cytokines. Receptor ligation by these cytokines leads to a series of events that includes the recruitment and activation of JAKs and the phosphorylation of various STATs, which in turn translocate to the nucleus where they transactivate various genes involved in cell differentiation, survival, apoptosis and proliferation.

Severe combined immunodeficiency

(SCID). A primary (inherited) immunodeficiency characterized by defects in cell-mediated and humoral immune responses. Affected infants commonly die within the first year of life owing to recurrent infections. Mutations in approximately ten different genes have been described to cause this condition, but defects in the common cytokine receptor γ-chain (γc) are the most common and result in X-linked SCID. Other genes that are mutated in patients with SCID include those encoding Janus kinase 3 (JAK3), recombination activating gene 1 (RAG1) and RAG2, IL-7 receptor α-chain (IL-7Rα) and adenosine deaminase.

pro-B cell

A cell at the earliest stage of B cell development in the bone marrow. These cells are characterized by incomplete immunoglobulin heavy-chain gene rearrangement and are defined as being CD19+ cytoplasmic IgM− or, sometimes, as B220+CD43+ (by the Hardy classification scheme).

pre-B cell

A cell at a stage of B cell development in the bone marrow that is characterized by complete immunoglobulin heavy-chain gene rearrangement in the absence of immunoglobulin light-chain gene rearrangement. These cells express the pre-B cell receptor, which comprises a pseudo light chain and a heavy chain. They are phenotypically CD19+ cytoplasmic IgM+ or are sometimes defined as being B220+CD43− cell surface IgM− (by the Hardy classification scheme).

Sepsis

A systemic response to severe infection or tissue damage, leading to a hyperactive and unbalanced network of pro-inflammatory mediators. Vascular permeability, cardiac function and metabolic balance are affected, resulting in tissue necrosis, multi-organ failure and death.

Delayed-type hypersensitivity

(DTH). A cellular immune response to antigen that develops over ∼24–72 hours with the infiltration of T cells and monocytes, and is dependent on the production of T helper 1 cell-specific cytokines.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mackall, C., Fry, T. & Gress, R. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 11, 330–342 (2011). https://doi.org/10.1038/nri2970

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2970

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing