Interleukin 7 Explained

Interleukin 7 (IL-7) is a protein[1] that in humans is encoded by the IL7 gene.[2] [3] [4]

IL-7 is a hematopoietic growth factor secreted by stromal cells in the bone marrow and thymus. It is also produced by keratinocytes,[5] dendritic cells,[6] hepatocytes,[7] neurons, and epithelial cells,[8] but is not produced by normal lymphocytes.[9] A study also demonstrated how the autocrine production of the IL-7 cytokine mediated by T-cell acute lymphoblastic leukemia (T-ALL) can be involved in the oncogenic development of T-ALL and offer novel insights into T-ALL spreading. [10]

Structure

The three-dimensional structure of IL-7 in complex with the ectodomain of IL-7 receptor has been determined using X-ray diffraction.[11]

Function

Lymphocyte maturation

IL-7 stimulates the differentiation of multipotent (pluripotent) hematopoietic stem cells into lymphoid progenitor cells (as opposed to myeloid progenitor cells where differentiation is stimulated by IL-3). It also stimulates proliferation of all cells in the lymphoid lineage (B cells, T cells and NK cells). It is important for proliferation during certain stages of B-cell maturation, T and NK cell survival, development and homeostasis.

IL-7 is a cytokine important for B and T cell development. This cytokine and the hepatocyte growth factor (HGF) form a heterodimer that functions as a pre-pro-B cell growth-stimulating factor. This cytokine is found to be a cofactor for V(D)J rearrangement of the T cell receptor beta (TCRß) during early T cell development.[12] This cytokine can be produced locally by intestinal epithelial and epithelial goblet cells, and may serve as a regulatory factor for intestinal mucosal lymphocytes. Knockout studies in mice suggested that this cytokine plays an essential role in lymphoid cell survival.[13]

IL-7 signaling

IL-7 binds to the IL-7 receptor, a heterodimer consisting of Interleukin-7 receptor alpha and common gamma chain receptor.[14] Binding results in a cascade of signals important for T-cell development within the thymus and survival within the periphery. Knockout mice which genetically lack IL-7 receptor exhibit thymic atrophy, arrest of T-cell development at the double positive stage, and severe lymphopenia. Administration of IL-7 to mice results in an increase in recent thymic emigrants, increases in B and T cells, and increased recovery of T cells after cyclophosphamide administration or after bone marrow transplantation.

Disease

Cancer

IL-7 promotes hematological malignancies (acute lymphoblastic leukemia, T cell lymphoma).[15]

Viral Infections

Elevated levels of IL-7 have also been detected in the plasma of HIV-infected patients.[16]

Clinical application

IL-7 as an immunotherapy agent has been examined in many pre-clinical animal studies and more recently in human clinical trials for various malignancies and during HIV infection.[9] [17]

Cancer

Recombinant IL-7 has been safely administered to patients in several phase I and II clinical trials. A human study of IL-7 in patients with cancer demonstrated that administration of this cytokine can transiently disrupt the homeostasis of both CD8+ and CD4+ T cells with a commensurate decrease in the percentage of CD4+CD25+Foxp3+ T regulatory cells.[18] No objective cancer regression was observed, however a dose limiting toxicity (DLT) was not reached in this study due to the development of neutralizing antibodies against the recombinant cytokine.

HIV infection

Associated with antiretroviral therapy, IL-7 administration decreased local and systemic inflammations in patients that had incomplete T-cell reconstitution. These results suggest that IL-7 therapy can possibly improve the quality of life of those patients.[19]

Transplantation

IL-7 could also be beneficial in improving immune recovery after allogenic stem cell transplant.[20]

Further reading

Notes and References

  1. 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 . 333 . 6173 . 571–3 . June 1988 . 3259677 . 10.1038/333571a0 . 1988Natur.333..571N . 4315541 .
  2. 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. . 86 . 1 . 302–6 . January 1989 . 2643102 . 286452 . 10.1073/pnas.86.1.302. 1989PNAS...86..302G . free .
  3. Sutherland GR, Baker E, Fernandez KE, Callen DF, Goodwin RG, Lupton S, Namen AE, Shannon MF, Vadas MA . Grant Robert Sutherland . The gene for human interleukin 7 (IL7) is at 8q12-13 . Hum. Genet. . 82 . 4 . 371–2 . July 1989 . 2786840 . 10.1007/BF00274000. 30870920 .
  4. Lupton SD, Gimpel S, Jerzy R, etal . Characterization of the human and murine IL-7 genes . J. Immunol. . 144 . 9 . 3592–601 . 1990 . 10.4049/jimmunol.144.9.3592 . 2329282 . 36007598 . free .
  5. Heufler C, Topar G, Grasseger A, etal . Interleukin 7 is produced by murine and human keratinocytes . J. Exp. Med. . 178 . 3 . 1109–14 . September 1993 . 8350050 . 2191157 . 10.1084/jem.178.3.1109.
  6. Kröncke R, Loppnow H, Flad HD, Gerdes J . Human follicular dendritic cells and vascular cells produce interleukin-7: a potential role for interleukin-7 in the germinal center reaction . Eur. J. Immunol. . 26 . 10 . 2541–4 . October 1996 . 8898972 . 10.1002/eji.1830261040 . 20992591 .
  7. Sawa Y, Arima Y, Ogura H, etal . Hepatic interleukin-7 expression regulates T cell responses . Immunity . 30 . 3 . 447–57 . March 2009 . 19285437 . 10.1016/j.immuni.2009.01.007 . free .
  8. Watanabe M, Ueno Y, Yajima T, etal . Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes . J. Clin. Invest. . 95 . 6 . 2945–53 . 1995 . 7769137 . 10.1172/JCI118002 . 295983 .
  9. Fry TJ, Mackall CL . Interleukin-7: from bench to clinic . Blood . 99 . 11 . 3892–904 . June 2002 . 12010786 . 10.1182/blood.V99.11.3892 . free .
  10. Buffière A, Uzan B, Aucagne R, Hermetet F, Mas M, Nassurdine S, Aznague A, Carmignac V, Tournier B, Bouchot O, Ballerini P, Barata JT, Bastie JN, Delva L, Pflumio F, Quéré R . T-cell acute lymphoblastic leukemia displays autocrine production of Interleukin-7 . Oncogene . 38 . 1 . 7357–7365 . November 2019 . 31417180. 10.1038/s41388-019-0921-4 . 199668368 .
  11. McElroy CA, Dohm JA, Walsh ST . Structural and biophysical studies of the human IL-7/IL-7Ralpha complex . Structure . 17 . 1 . 54–65 . January 2009 . 19141282 . 2654238 . 10.1016/j.str.2008.10.019 .
  12. Muegge K, Vila MP, Durum SK . Interleukin-7: a cofactor for V(D)J rearrangement of the T cell receptor beta gene . Science . 261 . 5117 . 93–5 . July 1993 . 7686307 . 10.1126/science.7686307. 1993Sci...261...93M.
  13. Web site: Entrez Gene: IL7 interleukin 7.
  14. Noguchi M, Nakamura Y, Russell SM, etal . Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor . Science . 262 . 5141 . 1877–80 . 1994 . 8266077 . 10.1126/science.8266077 . 1993Sci...262.1877N .
  15. Or R, Abdul-Hai A, Ben-Yehuda A . Reviewing the potential utility of interleukin-7 as a promoter of thymopoiesis and immune recovery . Cytokines Cell. Mol. Ther. . 4 . 4 . 287–94 . December 1998 . 10068062 .
  16. Napolitano LA, Grant RM, Deeks SG, etal . Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis . Nat. Med. . 7 . 1 . 73–9 . January 2001 . 11135619 . 10.1038/83381 . 22536639 .
  17. Fry TJ, Mackall CL . Interleukin-7 and immunorestoration in HIV: beyond the thymus . J. Hematother. Stem Cell Res. . 11 . 5 . 803–7 . 2003 . 12427286 . 10.1089/152581602760404603 .
  18. Rosenberg SA, Sportès C, Ahmadzadeh M, Fry TJ, Ngo LT, Schwarz SL, Stetler-Stevenson M, Morton KE, Mavroukakis SA, Morre M, Buffet R, Mackall CL, Gress RE . 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 . 3 . 313–9 . 2006 . 16699374 . 1473976 . 10.1097/01.cji.0000210386.55951.c2 .
  19. Sereti I, Estes JD, Thompson WL, Morcock DR, Fischl MA, etal . Decreases in Colonic and Systemic Inflammation in Chronic HIV Infection after IL-7 Administration . PLOS Pathogens . 10 . 1 . e1003890 . 2014. 10.1371/journal.ppat.1003890 . 24497828 . 3907377 . free .
  20. Snyder KM, Mackall CL, Fry TJ . IL-7 in allogeneic transplant: clinical promise and potential pitfalls . Leuk. Lymphoma . 47 . 7 . 1222–8 . July 2006 . 16923550 . 10.1080/10428190600555876 . 20531769 .

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