HGNC Approved Gene Symbol: IL7
Cytogenetic location: 8q21.13 Genomic coordinates (GRCh38): 8:78,675,044-78,805,463 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q21.13 | {?Epidermodysplasia verruciformis, susceptibility to, 5} | 618309 | Autosomal recessive | 3 |
IL7 is critical for early T-cell development and homeostasis of naive and memory CD8 (see 186910)-positive T cells. It signals through the IL7 receptor complex, which consists of the IL7R-alpha chain (IL7R; 146661) and the common IL2R-gamma chain (IL2RG; 308380) (summary by O'Connor et al., 2010).
Namen et al. (1988) described a factor derived from a stromal cell line that is capable of supporting the growth of pre-B cells in vitro in the absence of any stromal elements. Namen et al. (1988) later reported the molecular cloning of a cDNA encoding this factor, which they termed interleukin-7. They showed that recombinant murine IL-7 could replace murine bone marrow stromal cells in supporting the extended growth of both pre-B cells and pro-B cells.
Goodwin et al. (1989) isolated a cDNA encoding biologically active human interleukin-7 by hybridization with the homologous murine clone. Nucleotide sequence analysis indicated that this cDNA was capable of encoding a protein of 177 amino acids with a signal sequence of 25 amino acids and a calculated mass of 17.4 kD for the mature protein. Recombinant human interleukin-7 stimulated the proliferation of murine pre-B cells and was active on cells harvested from human bone marrow that are enriched for B-lineage progenitor cells.
Watanabe et al. (1995) provided insight into the interaction of mucosal lymphocytes and intestinal epithelial cells in regulating immune response in the intestinal mucosa. They presented findings suggesting that human intestinal epithelial cells and epithelial goblet cells produce IL7, and that locally produced IL7 may serve as a potent regulatory factor for intestinal mucosal lymphocytes.
B cells develop in the bone marrow from progenitor cells that have been designated pre-pro-B cells, pro-B cells (no immunoglobulin, or Ig, chains chosen), pre-B cells (which have selected a heavy chain but not a light chain), and finally B cells (which express both heavy and light chains of the Ig molecule). Differentiation of pre-pro-B cells to pro-B cells requires signaling through IL7 receptor (IL7R; 146661) mediated by the pre-pro-B cell growth-stimulating factor (PPBSF), which consists of IL7 and a 30-kD protein cofactor. By amino acid sequencing and RT-PCR analysis, Lai and Goldschneider (2001) determined that the PPBSF cofactor is the 30-kD beta chain of HGF (HGFB; 142409) produced independently of the 60-kD alpha chain of HGF. Formation of an IL7-HGFB heterodimer requires the presence of heparin sulfate. Functional analysis indicated that either IL7 or HGFB can maintain the viability of pre-pro-B cells, but only the heterodimer can stimulate their proliferation and differentiation into pro-B cells. Lai and Goldschneider (2001) concluded that PPBSF is a novel form of cytokine, a hybrid cytokine, consisting of the bioactive components of 2 unrelated cytokines. They proposed that through its heparin-binding and mitogenic properties, HGFB enables IL7 to participate in cognate interactions at the stromal cell surface and transduce signals effectively at low levels of IL7R.
Using FACS analysis, O'Connor et al. (2010) investigated the role of IL7 in memory CD8-positive T-cell responses in healthy individuals and individuals infected with human immunodeficiency virus (HIV; see 609423). When stimulated with a pool of cytomegalovirus, Epstein-Barr virus, and influenza peptides, CD8-positive T cells from healthy individuals showed good proliferation and IFNG (147570) production, and proliferation was further enhanced by the addition of exogenous IL7. In HIV-positive individuals, antigen enhanced IFNG production to a small degree, but it did not enhance proliferation, and there was no benefit from incubation with IL7. O'Connor et al. (2010) concluded that IL7 has a role in secondary immune responses and that its activity is impaired in memory CD8-positive T cells from HIV-positive individuals.
The report by Liu et al. (2010) suggesting a crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease was retracted.
Sutherland et al. (1989) used part of the gene cloned by Goodwin et al. (1989) for mapping the gene by Southern analysis of a mouse/human somatic cell hybrid panel and by in situ hybridization. By the combination of approaches, they demonstrated that IL7 is located on 8q12-q13. Brunton and Lupton (1990) described a sequence tagged site (STS) in the IL7 gene. (Olson et al. (1989) suggested this PCR-based method for identifying markers along the chromosomes. From the known sequence of a unique segment of the genome, it is possible to synthesize probes specific for that region, thus avoiding the logistical problems of storing and distributing probes.)
In 3 adult sibs, born of consanguineous Arab parents, with epidermodysplasia verruciformis-5 (EV5; 618309) Horev et al. (2015) identified a homozygous nonsense mutation in the IL7 gene (R69X; 146660.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. Patient serum levels of IL7 were very low or undetectable.
Carvalho et al. (2001) created mice deficient in Il7 by gene-targeting techniques. Mice lacking Il7 produced B cells exclusively during fetal and perinatal life. Bone marrow B lymphopoiesis was low 1 week after birth and ceased by 7 weeks. At all ages tested the number of splenic B cells was about 10-fold lower than in wildtype mice, though most were large, activated (B1) cells located in marginal zones but not germinal centers. There was also a 50-fold increase in the frequency of immunoglobulin M (IgM)- and IgG-secreting cells, and the concentration of T cell-dependent serum Ig was increased 3- to 5-fold. Carvalho et al. (2001) concluded that early but not mature B lymphopoiesis is IL7-independent and generates B1 cells and a normal-sized marginal zone B-lymphocyte compartment.
Since IL7 is required for normal T-cell development, Khaled et al. (2002) evaluated the role of BAX (600040) in vivo by generating mice deficient in both Bax and Il7r. Bax deficiency protected cells from death due to the absence of Il7 signaling up to 4 weeks of age. By 12 weeks of age, Bax- and Il7r-deficient mice exhibited a loss of thymic cellularity comparable to that observed in mice deficient in Il7r alone. Khaled et al. (2002) determined that Bad (603167) and Bim (BCL2L11; 603827) were also part of the death pathway repressed by Il7. Khaled et al. (2002) concluded that, in young mice, Bax is an essential protein in the death pathway induced by Il7 deficiency.
Oliver et al. (2004) generated mice lacking both Il7 and Bim. Lack of Bim compensated for lack of Il7 in the survival of B-cell precursors and immature B cells, but it had no impact on the requirement for Il7 in differentiation or proliferation of B-cell precursors. Oliver et al. (2004) concluded that BIM and IL7 cooperate to control the survival of B-cell precursors and that the ability of IL7 to counteract the death-inducing effects of BIM is necessary to maintain the number of B cells that exist in animals.
Using mice deficient in Il7r and/or the common cytokine receptor gamma chain, Il2rg (308380), Vosshenrich et al. (2003) determined the cytokines responsible for fetal and perinatal lymphopoiesis in the absence of Il7. Fetal and perinatal B-cell lymphopoiesis occurred in the bone marrow of Il2rg -/- mice until 12 weeks of age, but it was absent in Il7r -/- mice by 4 weeks of age. Lymphopoiesis in Il7r -/- mice was restricted to fetal liver and was dependent on the presence of thymic stromal lymphopoietin (TSLP; 607003). The residual lymphopoiesis that occurred in Il7r -/- mice was dependent on Flk2 (136351). Vosshenrich et al. (2003) concluded that TSLP is the main factor driving IL7-independent fetal and perinatal lymphopoiesis, although FLK2 is involved.
Seddon et al. (2003) noted that IL7 contributes to the homeostatic proliferation of CD8 (see 186910) memory T cells in lymphopenic hosts and can compensate for the lack of IL15 (600554). They investigated the role of IL7 in the maintenance of CD4 (186940) memory T cells using mice expressing an inducible Lck (153390) transgene to dissect the influence of T-cell receptor (TCR; see 186880) from IL7R signals. TCR signals were not required for long-term survival of polyclonal memory T cells, but the availability of IL7 was critical for the expansion and survival of CD4-positive memory cells.
Estrogen deficiency induces bone wasting and osteoclastogenesis, enhances T-cell production of TNF (191160), represses bone marrow levels of TGFB (190180), upregulates IL7 production, and increases T-cell lymphopoiesis. Ryan et al. (2005) reported that ovariectomy in mice expanded the T-cell pool by stimulating both peripheral T-cell expansion and thymic T-cell output, leading to increased bone loss. The T lymphopoiesis and bone loss following ovariectomy could be reduced by half by thymectomy and could be prevented completely by IL7 inhibition. Ryan et al. (2005) concluded that ovariectomy leading to estrogen deficiency disrupts bone and T-cell homeostasis in a manner mediated by enhanced IL7 stimulation of thymic and extrathymic T-cell growth.
Pellegrini et al. (2009) found that treatment of lymphocytic choriomeningitis virus (LCMV)-vaccinated pancreatic beta islet cell tumor-bearing mice with recombinant human IL7 daily for 2 weeks resulted in a more rapid onset of euglycemia or mild hyperglycemia and increased survival compared with control mice. The improved immune response was associated with increased Il6 (147620) production and augmented Th17-cell (see 603149) differentiation, as well as repression of Cblb (604491), a negative regulator of T-cell activation, and enhancement of Smurf2 (605532) expression, which antagonizes Tgfb signaling. In the absence of LCMV vaccination, IL7 was inefficient in promoting antitumor responses, in spite of homeostatic induction of T-cell proliferation. Pellegrini et al. (2009) concluded that the addition of IL7 to vaccination substantially increases antitumor immunity.
Pellegrini et al. (2011) found that treatment of mice infected with LCMV variant clone-13, a model of chronic viremia, with human IL7 increased the magnitude of the immune response and rescued LCMV-specific T-cell clones, as well as the naive T-cell pool. LCMV-specific T cells showed enhanced degranulation kinetics and cytokine production after treatment with IL7, along with effective viral clearance and downregulation of Pd1 (PDCD1; 600244) on T cells. IL7 promoted a cytokine milieu favoring immune activation and production of cytoprotective Il22 (605330), thereby limiting hepatotoxicity. IL7 also downregulated Socs3 (604176) in T cells via suppression of Foxo transcription factors (see 136533). Conditional deficiency of Socs3 in T cells replicated aspects of the effects of IL7 on mice infected with LCMV variant clone-13. Pellegrini et al. (2011) proposed that IL7 may be therapeutically useful in the treatment of chronic viremia.
In 3 adult sibs, born of consanguineous Arab parents, with epidermodysplasia verruciformis-5 (EV5; 618309) Horev et al. (2015) identified a homozygous c.205A-T transversion in the IL7 gene, resulting in an arg69-to-ter (R69X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. Patient serum levels of IL7 were very low or undetectable.
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O'Connor, A. M., Crawley, A. M., Angel, J. B. Interleukin-7 enhances memory CD8+ T-cell recall responses in health but its activity is impaired in human immunodeficiency virus infection. Immunology 131: 525-536, 2010. [PubMed: 20673240] [Full Text: https://doi.org/10.1111/j.1365-2567.2010.03325.x]
Oliver, P. M., Wang, M., Zhu, Y., White, J., Kappler, J., Marrack, P. Loss of Bim allows precursor B cell survival but not precursor B cell differentiation in the absence of interleukin 7. J. Exp. Med. 200: 1179-1187, 2004. [PubMed: 15520248] [Full Text: https://doi.org/10.1084/jem.20041129]
Olson, M., Hood, L., Cantor, C., Botstein, D. A common language for physical mapping of the human genome. Science 245: 1434-1435, 1989. [PubMed: 2781285] [Full Text: https://doi.org/10.1126/science.2781285]
Pellegrini, M., Calzascia, T., Elford, A. R., Shahinian, A., Lin, A. E., Dissanayake, D., Dhanji, S., Nguyen, L. T., Gronski, M. A., Morre, M., Assouline, B., Lahl, K., Sparwasser, T., Ohashi, P. S., Mak, T. W. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nature Med. 15: 528-536, 2009. Note: Erratum: Nature Med. 15: 819 only, 2009. [PubMed: 19396174] [Full Text: https://doi.org/10.1038/nm.1953]
Pellegrini, M., Calzascia, T., Toe, J. G., Preston, S. P., Lin, A. E., Elford, A. R., Shahinian, A., Lang, P. A., Lang, K. S., Morre, M., Assouline, B., Lahl, K., Sparwasser, T., Tedder, T. F., Paik, J., DePinho, R. A., Basta, S., Ohashi, P. S., Mak, T. W. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144: 601-613, 2011. [PubMed: 21295337] [Full Text: https://doi.org/10.1016/j.cell.2011.01.011]
Ryan, M. R., Shepherd, R., Leavey, J. K., Gao, Y., Grassi, F., Schnell, F. J., Qian, W.-P., Kersh, G. J., Weitzmann, M. N., Pacifici, R. An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency. Proc. Nat. Acad. Sci. 102: 16735-16740, 2005. [PubMed: 16267136] [Full Text: https://doi.org/10.1073/pnas.0505168102]
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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. 95: 2945-2953, 1995. [PubMed: 7769137] [Full Text: https://doi.org/10.1172/JCI118002]