Medicine:Interleukin 7

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Short description: Growth factor secreted by stromal cells in the bone marrow and thymus.


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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).[citation needed] It also stimulates proliferation of all cells in the lymphoid lineage (B cells, T cells and NK cells).[citation needed] It is important for proliferation during certain stages of B-cell maturation, T and NK cell survival, development and homeostasis.[citation needed]

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.[citation needed] Knockout studies in mice suggested that this cytokine plays an essential role in lymphoid cell survival.[13]

IL-7 signaling

IL-7 receptor and signaling, common γ chain (blue) and IL-7 receptor-α (green)

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]

References

  1. ↑ "Stimulation of B-cell progenitors by cloned murine interleukin-7". Nature 333 (6173): 571–3. June 1988. doi:10.1038/333571a0. PMID 3259677. Bibcode: 1988Natur.333..571N. 
  2. ↑ "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. doi:10.1073/pnas.86.1.302. PMID 2643102. Bibcode: 1989PNAS...86..302G. 
  3. ↑ "The gene for human interleukin 7 (IL7) is at 8q12-13". Hum. Genet. 82 (4): 371–2. July 1989. doi:10.1007/BF00274000. PMID 2786840. 
  4. ↑ "Characterization of the human and murine IL-7 genes". J. Immunol. 144 (9): 3592–601. 1990. doi:10.4049/jimmunol.144.9.3592. PMID 2329282. 
  5. ↑ "Interleukin 7 is produced by murine and human keratinocytes". J. Exp. Med. 178 (3): 1109–14. September 1993. doi:10.1084/jem.178.3.1109. PMID 8350050. 
  6. ↑ "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. doi:10.1002/eji.1830261040. PMID 8898972. 
  7. ↑ "Hepatic interleukin-7 expression regulates T cell responses". Immunity 30 (3): 447–57. March 2009. doi:10.1016/j.immuni.2009.01.007. PMID 19285437. 
  8. ↑ "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. doi:10.1172/JCI118002. PMID 7769137. 
  9. ↑ 9.0 9.1 "Interleukin-7: from bench to clinic". Blood 99 (11): 3892–904. June 2002. doi:10.1182/blood.V99.11.3892. PMID 12010786. 
  10. ↑ "T-cell acute lymphoblastic leukemia displays autocrine production of Interleukin-7". Oncogene 38 (1): 7357–7365. November 2019. doi:10.1038/s41388-019-0921-4. PMID 31417180. 
  11. ↑ "Structural and biophysical studies of the human IL-7/IL-7Ralpha complex". Structure 17 (1): 54–65. January 2009. doi:10.1016/j.str.2008.10.019. PMID 19141282. 
  12. ↑ "Interleukin-7: a cofactor for V(D)J rearrangement of the T cell receptor beta gene". Science 261 (5117): 93–5. July 1993. doi:10.1126/science.7686307. PMID 7686307. Bibcode: 1993Sci...261...93M. https://zenodo.org/record/1231227. 
  13. ↑ "Entrez Gene: IL7 interleukin 7". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3574. 
  14. ↑ "Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor". Science 262 (5141): 1877–80. 1994. doi:10.1126/science.8266077. PMID 8266077. Bibcode: 1993Sci...262.1877N. https://zenodo.org/record/1231251. 
  15. ↑ "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. PMID 10068062. 
  16. ↑ "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. doi:10.1038/83381. PMID 11135619. 
  17. ↑ "Interleukin-7 and immunorestoration in HIV: beyond the thymus". J. Hematother. Stem Cell Res. 11 (5): 803–7. 2003. doi:10.1089/152581602760404603. PMID 12427286. https://zenodo.org/record/1235225. 
  18. ↑ "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. doi:10.1097/01.cji.0000210386.55951.c2. PMID 16699374. 
  19. ↑ "Decreases in Colonic and Systemic Inflammation in Chronic HIV Infection after IL-7 Administration". PLOS Pathogens 10 (1): e1003890. 2014. doi:10.1371/journal.ppat.1003890. PMID 24497828. 
  20. ↑ "IL-7 in allogeneic transplant: clinical promise and potential pitfalls". Leuk. Lymphoma 47 (7): 1222–8. July 2006. doi:10.1080/10428190600555876. PMID 16923550. https://zenodo.org/record/1234479. 

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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