HGNC Approved Gene Symbol:IL7
Cytogenetic location:8q21.13 Genomic coordinates(GRCh38) :8:78,675,044-78,805,463 (from NCBI)
IL7 is critical for early T-cell development and homeostasis of naive and memory CD8 (see186910)-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 byO'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; see609423). 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 byLiu et al. (2010) suggesting a crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease was retracted.
The report ofKosumi et al. (2020) was retracted in the basis of an error involving their findings for patient 2. However, in their retraction, the authors stated that the findings for patient 1 were correct. Patient 1 ofKosumi et al. (2020) was followed up as patient 3 in the report ofArango-Franco et al. (2024) (see146660.0003).
Sutherland et al. (1989) used part of the gene cloned byGoodwin 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.)
Immunodeficiency 130 with HPV-Related Verrucosis
In 3 adult sibs, born of consanguineous Arab parents, with immunodeficiency-130 with HPV-related verrucosis (IMD130;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.
In 3 unrelated patients (P1, P2, and P3) with IMD130,Arango-Franco et al. (2024) identified homozygous loss-of-function mutations in the IL7 gene (146660.0002 and146660.0003). The mutations, which were found by exome or genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families.Arango-Franco et al. (2024) also reviewed the 3 sibs from the Arab family previously reported byHorev et al. (2015) who carried a homozygous R69X mutation (146660.0001), and reported functional studies of this variant. Supernatants from HEK293 cells transfected with the mutations had normal levels of IL7 mRNA, but no detectable IL7 protein. No IL7 was detected in plasma samples from all 6 patients. Transfected cells and patient-derived cells from P1 and P2 did not induce STAT5 (601511) phosphorylation, consistent with a loss-of-function effect. Detailed immunologic flow cytometric studies of patient blood showed low levels and impaired development of specific T lymphocyte subsets, including alpha/beta T cells (CD3+, CD4+, and CD8+ T cells), mucosal-associated invariant T cells (MAIT), invariant NK T cells, naive T cells, central memory T cells, Th1*, and Th17. By contrast, CD4+ and CD8+ effector T cells were increased, and terminally differentiated CD4+ and CD8+ T cells were in the normal range. There was impaired T-cell proliferation in response to stimulation and decreased cytokine production. The patients had impaired thymic T-cell output and development: P1 had a remnant thymus (at age 21), P2 and P3 had no thymic tissue (at age 56), and P1 and P2 had decreased TRECs compared to controls. Myeloid cell, NK cell, and B cell counts and function were relatively preserved, and the patients were able to mount detectable humoral responses. RNA-seq analysis of patient cells showed altered transcriptional profiles of both T and B cells, and some NK cells. Of note, flow cytometry indicated increased T(regs), but RNA-seq indicated decreased T(regs).
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 (see186910) 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; see186880) 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 (see603149) 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 (see136533). 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 immunodeficiency-130 with HPV-related verrucosis (IMD130;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.
Variant Function
Arango-Franco et al. (2024) revisited these patients (P4, P5, and P6) and showed that the R69X mutation resulted in a loss of function.
In 2 unrelated patients from Colombia, P1 from consanguineous kindred A and P2 from nonconsanguineous kindred B, with immunodeficiency-130 with HPV-related verrucosis (IMD130;618309),Arango-Franco et al. (2024) identified a homozygous 1-bp deletion (c.284del, NM_000880.4) in exon 4 of the IL7 gene, resulting in a frameshift and premature termination (Asn95IlefsTer11). The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Haplotype analysis was consistent with a founder effect. Functional studies of the variant indicated a loss-of-function effect.
In a 58-year-old woman (P3), born of consanguineous Japanese parents, with immunodeficiency-130 with HPV-related verrucosis (IMD130;618309),Arango-Franco et al. (2024) identified a homozygous c.3G-A transition (c.3G-A, NM_000880.4) in the initiation codon of the IL7 gene, resulting in a met1-to-? substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The patient had previously been reported byKosumi et al. (2020) as P1. Functional studies of the variant were consistent with a loss-of-function effect. The patient had numerous HPV7 (alpha)-positive verrucae on her limbs since the teenage years and later developed squamous cell carcinoma on a finger and buttocks. She had no recurrent infections and no adverse reactions to vaccination, including BCG. Laboratory studies showed CD4+ T-cell lymphopenia and antiphospholipid syndrome.
Arango-Franco, C. A., Ogishi, M., Unger, S., Delmonte, O. M., Orrego, J. C., Yatim, A., Velasquez-Lopera, M. M., Zea-Vera, A. F., Bohlen, J., Chbihi, M., Fayand, A., Sanchez, J. P., and 59 others.IL-7-dependent and -independent lineages of IL-7R-dependent human T cells. J. Clin. Invest. 134: e180251, 2024. [PubMed:39352394,related citations] [Full Text]
Brunton, L. L., Lupton, S. D.An STS in the human IL7 gene located at 18q12-13. Nucleic Acids Res. 18: 1315 only, 1990. Note: Erratum: Nucleic Acids Res. 18: 2852 only, 1990. [PubMed:2320434,related citations] [Full Text]
Carvalho, T. L., Mota-Santos, T., Cumano, A., Demengeot, J., Vieira, P.Arrested B lymphopoiesis and persistence of activated B cells in adult interleukin 7-/- mice. J. Exp. Med. 194: 1141-1150, 2001. [PubMed:11602642,related citations] [Full Text]
Goodwin, R. G., Lupton, S., Schmierer, A., Hjerrild, K. J., Jerzy, R., Clevenger, W., Gillis, S., Cosman, D., Namen, A. E.Human interleukin 7: molecular cloning and growth factor activity on human and murine B-lineage cells. Proc. Nat. Acad. Sci. 86: 302-306, 1989. [PubMed:2643102,related citations] [Full Text]
Horev, L., Unger, S., Molho-Pessach, V., Meir, T., Maly, A., Stpensky, P., Zamir, M., Keller, B., Babay, S., Warnatz, K., Ramot, Y., Zlotogorski, A.Generalized verrucosis and HPV-3 susceptibility associated with CD4 T-cell lymphopenia caused by inherited human interleukin-7 deficiency. (Letter) J. Am. Acad. Derm. 72: 1082-1084, 2015. [PubMed:25981006,related citations] [Full Text]
Khaled, A. R., Li, W. Q., Huang, J., Fry, T. J., Khaled, A. S., Mackall, C. L., Muegge, K., Young, H. A., Durum, S. K.Bax deficiency partially corrects interleukin-7 receptor-alpha deficiency. Immunity 17: 561-573, 2002. [PubMed:12433363,related citations] [Full Text]
Kosumi, H., Natsuga, K., Takashima, S., Miyauchi, T., Huang, Y. T., Nomura, T., Yanagi, T., Huang, H. Y., Chiu, F. P., Chen, P. C., Hsu, C. K., Shimizu, H.Two cases of interleukin-7-deficient generalized verrucosis. Clin. Infect. Dis. 71: 1561-1563, 2020. Note: Retraction: Clin. Infect. Dis. 16Apr, 2024. Advance Electronic Publication. [PubMed:31900472,related citations] [Full Text]
Lai, L., Goldschneider, I.Cutting edge: identification of a hybrid cytokine consisting of IL-7 and the beta-chain of the hepatocyte growth factor/scatter factor. J. Immun. 167: 3550-3554, 2001. [PubMed:11564764,related citations] [Full Text]
Liu, X., Leung, S., Wang, C., Tan, Z., Wang, J., Guo, T. B., Fang, L., Zhao, Y., Wan, B., Qin, X., Lu, L., Li, R., Pan, H., Song, M., Liu, A., Hong, J., Lu, H., Zhang, J. Z.Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. Nature Med. 16: 191-197, 2010. Note: Retraction: Nature Med. 19: 1673 only, 2013. [PubMed:20062065,related citations] [Full Text]
Namen, A. E., Lupton, S., Hjerrild, K., Wignall, J., Mochizuki, D. Y., Schmierer, A., Mosley, B., March, C. J., Urdal, D., Gillis, S., Cosman, D., Goodwin, R. G.Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature 333: 571-573, 1988. [PubMed:3259677,related citations] [Full Text]
Namen, A. E., Schmierer, A. E., March, C. J., Overell, R. W., Park, L. S., Urdal, D. L., Mochizuki, D. Y.B-cell precursor growth-promoting activity: purification and characterization of a growth factor active on lymphocyte precursors. J. Exp. Med. 167: 988-1002, 1988. [PubMed:3258354,related citations] [Full Text]
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,related citations] [Full Text]
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,related citations] [Full Text]
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,related citations] [Full Text]
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,related citations] [Full Text]
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,related citations] [Full Text]
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,related citations] [Full Text]
Seddon, B., Tomlinson, P., Zamoyska, R.Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nature Immun. 4: 680-686, 2003. [PubMed:12808452,related citations] [Full Text]
Sutherland, G. R., Baker, E., Fernandez, K. E. W., Callen, D. F., Goodwin, R. G., Lupton, S., Namen, A. E., Shannon, M. F., Vadas, M. A.The gene for human interleukin 7 (IL7) is at 8q12-13. Hum. Genet. 82: 371-372, 1989. [PubMed:2786840,related citations] [Full Text]
Vosshenrich, C. A. J., Cumano, A., Muller, W., Di Santo, J. P., Vieira, P.Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development. Nature Immun. 4: 773-779, 2003. [PubMed:12872121,related citations] [Full Text]
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,related citations] [Full Text]
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 | Immunodeficiency 130 with HPV-related verrucosis | 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.
The report of Kosumi et al. (2020) was retracted in the basis of an error involving their findings for patient 2. However, in their retraction, the authors stated that the findings for patient 1 were correct. Patient 1 of Kosumi et al. (2020) was followed up as patient 3 in the report of Arango-Franco et al. (2024) (see 146660.0003).
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.)
Immunodeficiency 130 with HPV-Related Verrucosis
In 3 adult sibs, born of consanguineous Arab parents, with immunodeficiency-130 with HPV-related verrucosis (IMD130; 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.
In 3 unrelated patients (P1, P2, and P3) with IMD130, Arango-Franco et al. (2024) identified homozygous loss-of-function mutations in the IL7 gene (146660.0002 and 146660.0003). The mutations, which were found by exome or genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Arango-Franco et al. (2024) also reviewed the 3 sibs from the Arab family previously reported by Horev et al. (2015) who carried a homozygous R69X mutation (146660.0001), and reported functional studies of this variant. Supernatants from HEK293 cells transfected with the mutations had normal levels of IL7 mRNA, but no detectable IL7 protein. No IL7 was detected in plasma samples from all 6 patients. Transfected cells and patient-derived cells from P1 and P2 did not induce STAT5 (601511) phosphorylation, consistent with a loss-of-function effect. Detailed immunologic flow cytometric studies of patient blood showed low levels and impaired development of specific T lymphocyte subsets, including alpha/beta T cells (CD3+, CD4+, and CD8+ T cells), mucosal-associated invariant T cells (MAIT), invariant NK T cells, naive T cells, central memory T cells, Th1*, and Th17. By contrast, CD4+ and CD8+ effector T cells were increased, and terminally differentiated CD4+ and CD8+ T cells were in the normal range. There was impaired T-cell proliferation in response to stimulation and decreased cytokine production. The patients had impaired thymic T-cell output and development: P1 had a remnant thymus (at age 21), P2 and P3 had no thymic tissue (at age 56), and P1 and P2 had decreased TRECs compared to controls. Myeloid cell, NK cell, and B cell counts and function were relatively preserved, and the patients were able to mount detectable humoral responses. RNA-seq analysis of patient cells showed altered transcriptional profiles of both T and B cells, and some NK cells. Of note, flow cytometry indicated increased T(regs), but RNA-seq indicated decreased T(regs).
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 immunodeficiency-130 with HPV-related verrucosis (IMD130; 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.
Variant Function
Arango-Franco et al. (2024) revisited these patients (P4, P5, and P6) and showed that the R69X mutation resulted in a loss of function.
In 2 unrelated patients from Colombia, P1 from consanguineous kindred A and P2 from nonconsanguineous kindred B, with immunodeficiency-130 with HPV-related verrucosis (IMD130; 618309), Arango-Franco et al. (2024) identified a homozygous 1-bp deletion (c.284del, NM_000880.4) in exon 4 of the IL7 gene, resulting in a frameshift and premature termination (Asn95IlefsTer11). The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Haplotype analysis was consistent with a founder effect. Functional studies of the variant indicated a loss-of-function effect.
In a 58-year-old woman (P3), born of consanguineous Japanese parents, with immunodeficiency-130 with HPV-related verrucosis (IMD130; 618309), Arango-Franco et al. (2024) identified a homozygous c.3G-A transition (c.3G-A, NM_000880.4) in the initiation codon of the IL7 gene, resulting in a met1-to-? substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The patient had previously been reported by Kosumi et al. (2020) as P1. Functional studies of the variant were consistent with a loss-of-function effect. The patient had numerous HPV7 (alpha)-positive verrucae on her limbs since the teenage years and later developed squamous cell carcinoma on a finger and buttocks. She had no recurrent infections and no adverse reactions to vaccination, including BCG. Laboratory studies showed CD4+ T-cell lymphopenia and antiphospholipid syndrome.
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