CD27 explained

CD27 is a member of the tumor necrosis factor receptor superfamily.^[1] It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule, and is the target of an anti-cancer drug in clinical trials.^[2]

Expression

During mouse embryonic development, specific (medium) expression levels of CD27 (in addition to high cKit,^{[3] [4]} medium Gata2,^{[5] [6]} and high CD31 expression levels) define the very first adult definitive hematopoietic stem cells generated in the aorta-gonad-mesonephros region. Furthermore, CD27 is expressed on both naïve and activated effector T cells as well as NK cells and activated B cells. It is a type I transmembrane protein with cysteine-rich domains, but once T cells have become activated, a soluble form of CD27 can be shed.

Function

The protein encoded by this gene is a member of the TNF-receptor superfamily.^[7] This receptor is required for generation and long-term maintenance of T cell immunity. It binds to ligand CD70, and plays a key role in regulating B-cell activation and immunoglobulin synthesis.

When CD27 binds CD70, a signaling cascade leads to the differentiation and clonal expansion of T cells. The cascade also results in improved survival and memory of cytotoxic T cells and increased production of certain cytokines.^[8] This receptor transduces signals that lead to the activation of NF-κB and MAPK8/JNK. Adaptor proteins TRAF2, TRAF3, and TRAF5 have been shown to mediate the signaling process of this receptor via ubiquitination. CD27-binding protein (SIVA), a proapoptotic protein, can bind to this receptor and is thought to play an important role in the apoptosis induced by this receptor.^[9]

In murine γδ T cells its expression has been correlated with the secretion of IFNγ.^[10]

Clinical significance

As a drug target

Varlilumab is an IgG1 antibody that binds to CD27 and is an experimental cancer treatment. This agonist antibody stimulates CD27 when it binds. The drug is in early clinical trials and appears to stimulate T cells and increase production of cytokines such as interferon-gamma.

Interactions

CD27 has been shown to interact with SIVA1,^[11] TRAF2^{[12] [13]} and TRAF3.^{[12] [13]}

Mutations

Some mutations can decrease the expression of CD27. Three such mutations, C53Y, C96Y, and R107C, are located in the cysteine-rich domains of CD27.

Further reading

• Lens SM, de Jong R, Hintzen RQ, Koopman G, van Lier RA, van Oers RH . CD27-CD70 interaction: unravelling its implication in normal and neoplastic B-cell growth . Leukemia & Lymphoma . 18 . 1–2 . 51–9 . June 1995 . 8580829 . 10.3109/10428199509064922 .
• Agematsu K . Memory B cells and CD27 . Histology and Histopathology . 15 . 2 . 573–6 . April 2000 . 10809378 . 10.14670/HH-15.573 .
• van Baarle D, Kostense S, van Oers MH, Hamann D, Miedema F . Failing immune control as a result of impaired CD8+ T-cell maturation: CD27 might provide a clue . Trends in Immunology . 23 . 12 . 586–91 . December 2002 . 12464570 . 10.1016/S1471-4906(02)02326-8 .
• Dörner T, Lipsky PE . Correlation of circulating CD27high plasma cells and disease activity in systemic lupus erythematosus . Lupus . 13 . 5 . 283–9 . 2005 . 15230280 . 10.1191/0961203304lu1014oa . 34654758 .

Notes and References

1. Buchan SL, Rogel A, Al-Shamkhani A . The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy . Blood . 131 . 1 . 39–48 . January 2018 . 29118006 . 10.1182/blood-2017-07-741025 . free .
2. Sturgill ER . TNFR agonists: a review of current biologics targeting OX40, 4-1BB, CD27, and GITR . American Journal of Hematology/Oncology . November 2017 . 13 . 11 . 4–15 .
3. Sánchez MJ, Holmes A, Miles C, Dzierzak E . Characterization of the first definitive hematopoietic stem cells in the AGM and liver of the mouse embryo . Immunity . 5 . 6 . 513–25 . December 1996 . 8986712 . 10.1016/s1074-7613(00)80267-8 . free .
4. Vink CS, Calero-Nieto FJ, Wang X, Maglitto A, Mariani SA, Jawaid W, Göttgens B, Dzierzak E . 6 . Iterative Single-Cell Analyses Define the Transcriptome of the First Functional Hematopoietic Stem Cells . Cell Reports . 31 . 6 . 107627 . May 2020 . 32402290 . 7225750 . 10.1016/j.celrep.2020.107627 .
5. Kaimakis P, de Pater E, Eich C, Solaimani Kartalaei P, Kauts ML, Vink CS, van der Linden R, Jaegle M, Yokomizo T, Meijer D, Dzierzak E . 6 . Functional and molecular characterization of mouse Gata2-independent hematopoietic progenitors . Blood . 127 . 11 . 1426–37 . March 2016 . 26834239 . 4797020 . 10.1182/blood-2015-10-673749 .
6. Eich C, Arlt J, Vink CS, Solaimani Kartalaei P, Kaimakis P, Mariani SA, van der Linden R, van Cappellen WA, Dzierzak E . 6 . In vivo single cell analysis reveals Gata2 dynamics in cells transitioning to hematopoietic fate . The Journal of Experimental Medicine . 215 . 1 . 233–248 . January 2018 . 29217535 . 5748852 . 10.1084/jem.20170807 .
7. Burugu S, Dancsok AR, Nielsen TO . Emerging targets in cancer immunotherapy . Seminars in Cancer Biology . 52 . Pt 2 . 39–52 . October 2018 . 28987965 . 10.1016/j.semcancer.2017.10.001 . Immuno-oncological biomarkers . 33534342 .
8. Bullock TN . Stimulating CD27 to quantitatively and qualitatively shape adaptive immunity to cancer . Current Opinion in Immunology . 45 . 82–88 . April 2017 . 28319731 . 10.1016/j.coi.2017.02.001 . 5449212 .
9. Web site: Entrez Gene: CD27 CD27 molecule.
10. Ribot JC, deBarros A, Pang DJ, Neves JF, Peperzak V, Roberts SJ, Girardi M, Borst J, Hayday AC, Pennington DJ, Silva-Santos B . 6 . CD27 is a thymic determinant of the balance between interferon-gamma- and interleukin 17-producing gammadelta T cell subsets . Nature Immunology . 10 . 4 . 427–36 . April 2009 . 19270712 . 4167721 . 10.1038/ni.1717 .
11. Prasad KV, Ao Z, Yoon Y, Wu MX, Rizk M, Jacquot S, Schlossman SF . CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein . Proceedings of the National Academy of Sciences of the United States of America . 94 . 12 . 6346–51 . June 1997 . 9177220 . 21052 . 10.1073/pnas.94.12.6346 . 1997PNAS...94.6346P . free .
12. Yamamoto H, Kishimoto T, Minamoto S . NF-kappaB activation in CD27 signaling: involvement of TNF receptor-associated factors in its signaling and identification of functional region of CD27 . Journal of Immunology . 161 . 9 . 4753–9 . November 1998 . 10.4049/jimmunol.161.9.4753 . 9794406 . 22442601 .
13. Akiba H, Nakano H, Nishinaka S, Shindo M, Kobata T, Atsuta M, Morimoto C, Ware CF, Malinin NL, Wallach D, Yagita H, Okumura K . 6 . CD27, a member of the tumor necrosis factor receptor superfamily, activates NF-kappaB and stress-activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-kappaB-inducing kinase . The Journal of Biological Chemistry . 273 . 21 . 13353–8 . May 1998 . 9582383 . 10.1074/jbc.273.21.13353 . free .