# CD80

## Overview
CD80, also known as B7-1, is a protein encoded by the CD80 gene located on chromosome 3 in humans. This protein is a type I transmembrane receptor belonging to the immunoglobulin superfamily and plays a critical role in the regulation of immune responses. CD80 is primarily expressed on antigen-presenting cells (APCs) and is involved in the costimulatory process that is essential for T cell activation and survival. The protein interacts with two important T cell receptors, CD28 for stimulatory signals and CTLA-4 for inhibitory signals, which are crucial for the modulation of immune responses and maintenance of self-tolerance. The balance between these interactions influences various immune functions and has implications in autoimmunity, infection, and cancer (Zhao2019PD-L1:CD80; Soskic2021CD80).

## Structure
The CD80 protein, also known as B7-1, is a member of the immunoglobulin superfamily (IgSF) and is characterized by its structure which includes two extracellular immunoglobulin-like (Ig-like) domains: the Ig variable-like (IgV) domain and the Ig constant-like (IgC) domain. The IgV domain is primarily responsible for receptor interactions, specifically binding to the MYPPPY motif in the CDR3 region of CD28 and CTLA-4 receptors on T cells. This domain is structured as anti-parallel beta sandwiches, crucial for the protein's function (Girard2014CD80; Peach1995Both). 

The IgC domain, while not directly contacting CTLA-4, plays a significant role in stabilizing the structural integrity of the protein and is necessary for optimal receptor interaction (Girard2014CD80). Structural studies have shown that CD80 predominantly exists as a dimer, which is stabilized by hydrophobic interactions at the dimer interface (Girard2014CD80). 

Post-translational modifications such as glycosylation occur, with several potential N-linked glycosylation sites identified in both the IgV and IgC domains, although these modifications do not appear to significantly impact receptor binding (Peach1995Both). Additionally, a splice variant of CD80, which lacks the entire membrane proximal IgC domain, exhibits altered receptor binding characteristics, suggesting that this domain is essential for full receptor interaction (Peach1995Both).

## Function
CD80, also known as B7-1, is a protein encoded by the CD80 gene, primarily expressed on the surface of antigen-presenting cells (APCs) such as dendritic cells and macrophages. It plays a crucial role in the immune system by providing costimulatory signals necessary for T cell activation and survival. The interaction of CD80 with CD28 on T cells delivers a vital costimulatory signal that is essential for T cell activation, proliferation, and the prevention of anergy, a state of T cell unresponsiveness (Watanabe2019Increases). This interaction also promotes cytokine production, which is crucial for effective immune responses (Soskic2021CD80).

Additionally, CD80 interacts with CTLA-4, a receptor with a higher affinity than CD28, found on activated T cells. This interaction plays a regulatory role, helping to maintain immune homeostasis and prevent autoimmunity by potentially downregulating T cell responses (Watanabe2019Increases). CD80 is also expressed on T cells themselves, particularly on activated CD4+ T cells, indicating that CD80 expression can be intrinsic to T cells and not just acquired from APCs through ligand transfer (Soskic2021CD80).

In the context of regulatory T cells (Tregs), CD80's interaction with CTLA-4 is particularly significant as it supports Treg homeostasis and survival by modulating the competitive interactions between CTLA-4 and CD28, thereby influencing Treg proliferation and function (Soskic2021CD80). This highlights the dual functionality of CD80 in T cell modulation, acting as both a stimulatory and inhibitory molecule depending on the molecular interactions and the strength of T cell receptor engagement (Manzotti2002Inhibition).

## Clinical Significance
CD80, implicated in various health conditions, plays a significant role in bone health and immune-related diseases. Variants in the CD80 gene are associated with lumbar spine bone mineral density in postmenopausal women, suggesting its involvement in osteoporosis. Specifically, certain single nucleotide polymorphisms (SNPs) in CD80 have been linked to increased risk and severity of osteoporosis (Panach2017A). In the context of autoimmune diseases, CD80 interactions are crucial for maintaining immune tolerance. Abnormal expression or function of CD80 can lead to immune dysregulation, contributing to conditions such as rheumatoid arthritis (Lorenzetti2019Abatacept). Additionally, CD80 has been identified as a key player in minimal change disease (MCD), a nephrotic syndrome, where its increased expression on podocytes during relapse phases correlates with severe proteinuria (Cara-Fuentes2013CD80). In cancer, CD80's role is dual-faceted; it can act as a tumor suppressor or an enhancer of immune surveillance depending on its expression levels. For instance, in lung adenocarcinoma, higher CD80 expression is associated with better prognosis and enhanced immune response, whereas lower expression may facilitate tumor progression (Feng2023Significance). These findings underscore the clinical significance of CD80 in a range of pathological conditions, highlighting its potential as a therapeutic target.

## Interactions
CD80, also known as B7-1, is a protein expressed on antigen-presenting cells that interacts with several key proteins involved in immune regulation. CD80 forms cis-heterodimers with PD-L1, which inhibits the interaction between PD-L1 and PD-1, thereby modulating the PD-1 pathway known to suppress T cell activation (Zhao2019PD-L1:CD80). This interaction is crucial as it helps balance co-stimulatory and co-inhibitory signals during immune responses, ensuring effective immunity while preventing autoimmunity (Sugiura2019Restriction).

Additionally, CD80 interacts with CTLA-4 and CD28, playing a significant role in T cell costimulation and inhibition. The interaction with CTLA-4 is competitive, as both PD-L1 and CTLA-4 can bind to CD80, affecting the function of CTLA-4 (Zhao2019PD-L1:CD80). The presence of PD-L1 can inhibit CD80:CD80 homodimerization and prevent high-avidity CD80:CTLA-4 interactions, crucial for CTLA-4's function (Zhao2019PD-L1:CD80). Conversely, CD80's interaction with CD28 is resistant to inhibition by cis-PD-L1, highlighting a selective regulatory mechanism that favors stimulatory signaling via CD28 in the presence of PD-L1 (Zhao2019PD-L1:CD80).

Furthermore, CD80 can also form homodimers, and specific mutations in CD80 can disrupt both homodimerization and heterodimerization with PD-L1, indicating a complex regulatory mechanism at the protein interaction level (Zhao2019PD-L1:CD80). These interactions underscore the multifaceted role of CD80 in immune response modulation through various pathways.


## References


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[2. (Cara-Fuentes2013CD80) Gabriel Cara-Fuentes, Changli Wei, Alfons Segarra, Takuji Ishimoto, Christopher Rivard, Richard J. Johnson, Jochen Reiser, and Eduardo H. Garin. Cd80 and supar in patients with minimal change disease and focal segmental glomerulosclerosis: diagnostic and pathogenic significance. Pediatric Nephrology, 29(8):1363–1371, November 2013. URL: http://dx.doi.org/10.1007/s00467-013-2679-1, doi:10.1007/s00467-013-2679-1. (87 citations) 10.1007/s00467-013-2679-1](https://doi.org/10.1007/s00467-013-2679-1)

[3. (Sugiura2019Restriction) Daisuke Sugiura, Takumi Maruhashi, Il-mi Okazaki, Kenji Shimizu, Takeo K. Maeda, Tatsuya Takemoto, and Taku Okazaki. Restriction of pd-1 function by cis -pd-l1/cd80 interactions is required for optimal t cell responses. Science, 364(6440):558–566, May 2019. URL: http://dx.doi.org/10.1126/science.aav7062, doi:10.1126/science.aav7062. (317 citations) 10.1126/science.aav7062](https://doi.org/10.1126/science.aav7062)

[4. (Manzotti2002Inhibition) Claire N. Manzotti, Helen Tipping, Laura C. A. Perry, Karen I. Mead, Patrick J. Blair, Yong Zheng, and David M. Sansom. Inhibition of human t cell proliferation by ctla-4 utilizes cd80 and requires cd25+ regulatory t cells. European Journal of Immunology, 32(10):2888–2896, October 2002. URL: http://dx.doi.org/10.1002/1521-4141(2002010)32:10<2888::AID-IMMU2888>3.0.CO;2-F, doi:10.1002/1521-4141(2002010)32:10<2888::aid-immu2888>3.0.co;2-f. (186 citations) 10.1002/1521-4141(2002010)32:10<2888::AID-IMMU2888>3.0.CO;2-F](https://doi.org/10.1002/1521-4141(2002010)32:10)

[5. (Soskic2021CD80) Blagoje Soskic, Louisa E. Jeffery, Alan Kennedy, David H. Gardner, Tie Zheng Hou, Neil Halliday, Cayman Williams, Daniel Janman, Behzad Rowshanravan, Gideon M. Hirschfield, and David M. Sansom. Cd80 on human t cells is associated with foxp3 expression and supports treg homeostasis. Frontiers in Immunology, January 2021. URL: http://dx.doi.org/10.3389/fimmu.2020.577655, doi:10.3389/fimmu.2020.577655. (29 citations) 10.3389/fimmu.2020.577655](https://doi.org/10.3389/fimmu.2020.577655)

[6. (Panach2017A) L. Panach, E. Serna, J. J. Tarín, A. Cano, and M. Á. García-Pérez. A translational approach from an animal model identifies cd80 as a candidate gene for the study of bone phenotypes in postmenopausal women. Osteoporosis International, 28(8):2445–2455, May 2017. URL: http://dx.doi.org/10.1007/s00198-017-4061-9, doi:10.1007/s00198-017-4061-9. (13 citations) 10.1007/s00198-017-4061-9](https://doi.org/10.1007/s00198-017-4061-9)

[7. (Lorenzetti2019Abatacept) Raquel Lorenzetti, Iga Janowska, Cristian Roberto Smulski, Natalie Frede, Nadine Henneberger, Lea Walter, Marei-Theresa Schleyer, Janika M. Hüppe, Julian Staniek, Ulrich Salzer, Ana Venhoff, Arianna Troilo, Reinhard Edmund Voll, Nils Venhoff, Jens Thiel, and Marta Rizzi. Abatacept modulates cd80 and cd86 expression and memory formation in human b-cells. Journal of Autoimmunity, 101:145–152, July 2019. URL: http://dx.doi.org/10.1016/j.jaut.2019.04.016, doi:10.1016/j.jaut.2019.04.016. (85 citations) 10.1016/j.jaut.2019.04.016](https://doi.org/10.1016/j.jaut.2019.04.016)

[8. (Feng2023Significance) Wei Feng, Ziyi He, Liang Shi, Zheng Zhu, and Haitao Ma. Significance of cd80 as a prognostic and immunotherapeutic biomarker in lung adenocarcinoma. Biochemical Genetics, 61(5):1937–1966, March 2023. URL: http://dx.doi.org/10.1007/s10528-023-10343-7, doi:10.1007/s10528-023-10343-7. (1 citations) 10.1007/s10528-023-10343-7](https://doi.org/10.1007/s10528-023-10343-7)

[9. (Watanabe2019Increases) Ayano Watanabe, Naoya Inoue, Mikio Watanabe, Mayu Yamamoto, Haruka Ozaki, Yoh Hidaka, and Yoshinori Iwatani. Increases of cd80 and cd86 expression on peripheral blood cells and their gene polymorphisms in autoimmune thyroid disease. Immunological Investigations, 49(1–2):191–203, November 2019. URL: http://dx.doi.org/10.1080/08820139.2019.1688343, doi:10.1080/08820139.2019.1688343. (14 citations) 10.1080/08820139.2019.1688343](https://doi.org/10.1080/08820139.2019.1688343)

[10. (Girard2014CD80) Tanya Girard, Denis Gaucher, Mohamed El-Far, Gaëlle Breton, and Rafick-Pierre Sékaly. Cd80 and cd86 igc domains are important for quaternary structure, receptor binding and co-signaling function. Immunology Letters, 161(1):65–75, September 2014. URL: http://dx.doi.org/10.1016/j.imlet.2014.05.002, doi:10.1016/j.imlet.2014.05.002. (28 citations) 10.1016/j.imlet.2014.05.002](https://doi.org/10.1016/j.imlet.2014.05.002)

[11. (Peach1995Both) Robert J. Peach, Jürgen Bajorath, Joseph Naemura, Gina Leytze, JoAnne Greene, Alejandro Aruffo, and Peter S. Linsley. Both extracellular immunoglobin-like domains of cd80 contain residues critical for binding t cell surface receptors ctla-4 and cd28. Journal of Biological Chemistry, 270(36):21181–21187, September 1995. URL: http://dx.doi.org/10.1074/jbc.270.36.21181, doi:10.1074/jbc.270.36.21181. (250 citations) 10.1074/jbc.270.36.21181](https://doi.org/10.1074/jbc.270.36.21181)