Alternative titles; symbols
HGNC Approved Gene Symbol: CD70
SNOMEDCT: 1186715006;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:6,581,648-6,591,150 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Lymphoproliferative syndrome 3 | 618261 | Autosomal recessive | 3 |
CD70 is the ligand for CD27 (186711). The CD27-CD70 axis plays an important role in the generation and maintenance of T cell immunity, particularly during antiviral responses, including those for Epstein-Barr virus (EBV) (summary by Izawa et al., 2017).
To identify the ligand for CD27 (186711), Goodwin et al. (1993) screened a cDNA expression library derived from EBV-transformed human B cells (MP1 cells) with a fusion protein containing the extracellular domain of CD27. They isolated a cDNA encoding a protein with CD27-binding characteristics similar to those of the native cell surface CD27 ligand. The predicted 193-amino acid protein, which they called CD27L for 'CD27 ligand,' has a 20-amino acid hydrophilic N-terminal domain that lacks a signal sequence; an 18-amino acid hydrophobic region that presumably functions as a transmembrane anchor; and a C-terminal domain that contains 2 potential N-linked glycosylation sites. Based on these features, the authors suggested that the C-terminal domain of CD27L is extracellular, and thus classified CD27L as a type II transmembrane protein. CD27L is homologous to the ligands of the TNF receptor family, including TNF-alpha (191160), TNF-beta (153440), and the CD40 ligand (300386), showing 19 to 24% amino acid sequence identity in the extracellular region. Immunoprecipitation analysis of MP1 cell lysates using the CD27 fusion protein, followed by SDS-PAGE analysis, detected a predominant protein with an apparent Mr of approximately 50 kD. Since the calculated Mr of unmodified CD27L is 21 kD, Goodwin et al. (1993) suggested that the N-linked glycosylation sites of CD27L are used. By Northern blot analysis, they detected an approximately 1.2-kb CD27L transcript in tonsillar T cells, peripheral blood T cells, and some monocytic, B-, and pre-B-cell lines, but not in a lung fibroblast cell line.
CD70 is a surface antigen found on activated, but not resting, T and B lymphocytes. It was first detected on the surface of Hodgkin and Reed-Sternberg cells (see 236000). Using a monoclonal antibody against CD70 for fluorescence-activated cell sorting (FACS) of COS cells expressing cDNAs derived from EBV-transformed human B cells, Bowman et al. (1994) isolated cDNAs encoding CD70. Except for 2 basepair differences, the sequences of these CD70 cDNAs are identical to the sequence of the CD27L cDNA isolated by Goodwin et al. (1993).
Goodwin et al. (1993) demonstrated that CD27L induced proliferation of costimulated T cells and enhanced generation of cytolytic T cells.
In detailed cellular studies, Izawa et al. (2017) found that CD70 expression is induced in activated B cells upon stimulation, particularly when infected with EBV. CD27 is normally expressed at high levels on T cells, and the CD27-CD70 interaction forms a functional cluster or axis that plays a role in the immune surveillance of infected B cells by CD8+ T cells. CD70 delivers signals to T cells through CD27, which is necessary for CD8+ T-cell proliferation, maintenance, and effective control of EBV-infected cells. Izawa et al. (2017) also noted that CD70 is constitutively expressed by many B-cell malignancies, including EBV-associated malignancies, and that mutations in CD70 may represent a mechanism for malignant B cells to escape immune surveillance by T cells.
By fluorescence in situ hybridization, Goodwin et al. (1993) mapped the human CD27L gene to 19p13.
In a boy, born of consanguineous Egyptian parents, with lymphoproliferative syndrome-3 (LPFS3; 618261), Izawa et al. (2017) identified a homozygous nonsense mutation in the CD70 gene (R179X; 602840.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient-derived cells showed normal amounts of CD70 mRNA, but no detectable protein. Patient CD8+ T cells did not expand properly and showed markedly decreased cytotoxic activity against the patient's EBV-infected B cells compared to controls, but this could be restored by transduction of patient cells with CD70. Further studies showed that the intrinsic cytotoxicity function of CD8+ T cells was preserved, but the lack of CD70 on patient cells interrupted the CD70-CD27 signaling pathway for effector T cells. In addition, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells, further illustrating that this pathway is important for immune surveillance of activated B cells.
In 4 patients from 2 unrelated consanguineous families with LPFS3, Abolhassani et al. (2017) identified homozygous mutations in the CD70 gene (c.250delT, 602840.0002 and F186del, 602840.0003). Analysis of patient cells showed that the mutations either abolished CD70 protein expression or impaired binding to CD27, consistent with a loss of function. Detailed functional studies showed that patient CD8+ T cells were decreased in number compared to controls and had decreased cytotoxicity against patient EBV-infected B cells, which was caused by impaired activation by EBV-infected B cells rather than by impaired cytotoxicity of the T cells. In addition, patient memory CD8+ T cells showed decreased expression of CD244 (605554) and NKG2D (611817), which are receptors implicated in controlling EBV infection, consistent with the impaired killing of EBV-infected cells. The findings indicated that CD70-CD27 interactions play a nonredundant role in T and B cell-mediated immunity, especially for protection against EBV and humoral immunity.
Arens et al. (2001) generated transgenic mice constitutively expressing Cd70 on B cells. Cd70-transgenic mice had enhanced formation of both Cd4 (186940)-positive and Cd8 (see 186910)-positive effector/memory, Ifng (147570)-secreting T cells. B-cell numbers, however, progressively decreased in primary and secondary lymphoid organs due to Cd27-induced Ifng production. Cd70-transgenic/Ifng-deficient mice also had an activated T-cell compartment, but they retained normal B-cell numbers. Arens et al. (2001) concluded that the CD27/CD70 system is a potent activator of T cells in vivo.
Tesselaar et al. (2003) found that although activated T-cell numbers increased in Cd70-transgenic mice, there was a depletion of naive T cells. Flow cytometric analysis of peripheral lymph nodes demonstrated that T-cell numbers were only 10% of wildtype mice at 20 weeks of age. Moreover, after a healthy appearance over the first few months, Cd70-transgenic mice had reduced body mass at 5 months of age and succumbed to Pneumocystis carinii pneumonia, a hallmark of T-cell immunodeficiency, by 7 months of age. Tesselaar et al. (2003) concluded that Cd70-transgenic mice show persistent immune activation, similar to that in humans unable to control human immunodeficiency virus-1 replication, that can result in a state of lethal immunodeficiency.
In a boy, born of consanguineous Egyptian parents, with lymphoproliferative syndrome-3 (LPFS3; 618261), Izawa et al. (2017) identified a homozygous c.535C-T transition in exon 3 of the CD70 gene, resulting in an arg179-to-ter (R179X) substitution in the extracellular domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases, but was found once in the heterozygous state in the ExAC and an internal control database (frequency of 1.48 x 10(-5)). Patient-derived cells showed normal amounts of CD70 mRNA, but no detectable protein, consistent with a loss of function. In vitro functional studies in patient cells and HEK293 cells transfected with the mutation showed that the R179X mutation interrupted the ability of CD70 to recognize and bind to CD27 (186711).
In 2 sibs, born of consanguineous Persian parents (family 1), with lymphoproliferative syndrome-3 (LPFS3; 618261), Abolhassani et al. (2017) identified a homozygous 1-bp deletion (c.250delT) in exon 3 of the CD70 gene, resulting in a frameshift and premature termination (Ser84Profs27Ter). 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 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in 251 Iranian controls. Analysis of patient-derived cells showed normal CD70 mRNA, indicating minimal nonsense-mediated mRNA decay, but flow cytometric analysis showed absent protein levels and Western blot analysis of transfected HEK293 cells showed neither full-length nor truncated forms of CD70, consistent with a loss of expression and function.
In 2 sibs, born of consanguineous Turkish parents, with lymphoproliferative syndrome-3 (LPFS3; 618261), Abolhassani et al. (2017) identified a homozygous in-frame 3-bp deletion (c.555_557delCTT) in exon 3 of the CD70 gene, resulting in the deletion of residue phe186 (F186del). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Use of an antibody against the extracellular C-terminal portion of CD70 showed no expression on patient cells, although Western blot analysis using a polyclonal antibody upstream showed normal protein levels. In vitro studies in HEK293 cells showed that the mutation interrupted CD17 binding to CD70, consistent with a loss of function.
Abolhassani, H., Edwards, E. S. J., Ikinciogullari, A., Jing, H., Borte, S., Buggert, M., Du, L., Matsuda-Lennikov, M., Romano, R., Caridha, R., Bade, S., Zhang, Y., and 21 others. Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J. Exp. Med. 214: 91-106, 2017. [PubMed: 28011864] [Full Text: https://doi.org/10.1084/jem.20160849]
Arens, R., Tesselaar, K., Baars, P. A., van Schijndel, G. M. W., Hendriks, J., Pals, S. T., Krimpenfort, P., Borst, J., van Oers, M. H. J., van Lier, R. A. W. Constitutive CD27/CD70 interaction induces expansion of effector-type T cells and results in IFN-gamma-mediated B cell depletion. Immunity 15: 801-812, 2001. [PubMed: 11728341] [Full Text: https://doi.org/10.1016/s1074-7613(01)00236-9]
Bowman, M. R., Crimmins, M. A. V., Yetz-Aldape, J., Kriz, R., Kelleher, K., Herrmann, S. The cloning of CD70 and its identification as the ligand for CD27. J. Immun. 152: 1756-1761, 1994. [PubMed: 8120384]
Goodwin, R. G., Alderson, M. R., Smith, C. A., Armitage, R. J., VandenBos, T., Jerzy, R., Tough, T. W., Schoenborn, M. A., Davis-Smith, T., Hennen, K., Falk, B., Cosman, D., Baker, E., Sutherland, G. R., Grabstein, K. H., Farrah, T., Giri, J. G., Beckmann, M. P. Molecular and biological characterization of a ligand for CD27 defines a new family of cytokines with homology to tumor necrosis factor. Cell 73: 447-456, 1993. [PubMed: 8387892] [Full Text: https://doi.org/10.1016/0092-8674(93)90133-b]
Izawa, K., Martin, E., Soudais, C., Bruneau, J., Boutboul, D., Rodriguez, R., Lenoir, C., Hislop, A. D., Besson, C., Touzot, F., Picard, C., Callebaut, I., de Villartay, J.-P., Moshous, D., Fischer, A., Latour, S. Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. J. Exp. Med. 214: 73-89, 2017. [PubMed: 28011863] [Full Text: https://doi.org/10.1084/jem.20160784]
Tesselaar, K., Arens, R., van Schijndel, G. M. W., Baars, P. A., van der Valk, M. A., Borst, J., van Oers, M. H. J., van Lier, R. A. W. Lethal T cell immunodeficiency induced by chronic costimulation via CD27-CD70 interactions. Nature Immun. 4: 49-54, 2003. Note: Erratum: Nature Immun. 4: 295 only, 2003. [PubMed: 12469117] [Full Text: https://doi.org/10.1038/ni869]