The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein [5] in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor . [6] [7]
CD80 is a member of the B7 family, which consists of molecules present at APCs and their receptors present on the T-cells. [7] CD80 is present specifically on DC, activated B-cells, and macrophages, but also T-cells [7] [8] CD80 is also a transmembrane glycoprotein and a member of the Ig superfamily. [7] It is composed of 288 amino acids, and its mass is 33 kDa. [8] It consists of two Ig-like extracellular domains (208 AA), a transmembrane helical segment (21 AA), and a short cytoplasmic tail (25 AA). [7] [8] [9] The Ig-like extracellular domains are formed by single V-type and C2-type domains. [7] [6] [10] It is expressed as both monomers or dimers, but predominantly dimers. [7] [10] [11] These two forms exist in dynamic equilibrium. [12]
CD80 shares 25% of sequences with CD86; however, CD80 has a ten-fold higher affinity for CD28 and CTLA-4 than CD86. Moreover, CD80 interacts with its ligand with faster binding kinetics and slower dissociation constants than CD86. Both human CD80 and CD86 are located at chromosome 3; the exact region is 3q13.3-q21. [7]
Human and murine CD80 share approximately 44% of sequences. Also both human and murine CD80 are able to cross-react with both human and murine CD28. This indicates that the binding site of CD80 is conserved. [7] [12]
CD80 can be found on the surface of various immune cells, including B-cells, monocytes, or T-cells, but most typically at antigen-presenting cells (APCs) such as dendritic cells. [6] [7] [13] CD80 has a crucial role in modulating T-cell immune function as a checkpoint protein at the immunological synapse. [14]
CD80 is the ligand for the proteins CD28 (for autoregulation and intercellular association) and CTLA-4 (for attenuation of regulation and cellular disassociation) found on the surface of T-cells. [6] [13] Interaction of CD80 with CD28 triggers costimulatory signals and results in enhanced and sustained T-cell activation. In contrast, contrary interaction of CD80 with CTLA-4 inhibits parts of T-cell effector function. These two ligands are structurally homologous, and they compete with each other for binding sites. [14] However, the bond with CTLA-4 has up to 2500 fold higher avidity than with CD28. [7] This illustrates that inhibitory interaction with CTLA-4 is predominant. [14]
CD80 binds to CD28 and CTLA-4 with lower affinity and fast binding kinetics (Kd = 4 μM for CD28 and 0.42 μM for CTLA-4), allowing for quick interactions between the communicating cells. [15] These interactions result in an important costimulatory signal in the immunological synapse between antigen-presenting cells, B-cells, dendritic cells and T-cells that result in T and B-cell activation, proliferation and differentiation. [11]
When stimulated by CD80, T helper cells preferentially differentiate into Th1 cells. [11] CD80 is an essential component in dendritic cell licensing and cytotoxic T-cell activation. When the major histocompatibility complex class II (MHC class II)-peptide complex on a dendritic cell interacts with the receptor on a T helper cell, CD80 is up-regulated, licensing the dendritic cell and allowing for interaction between the dendritic cell and CD 8+ T-cells via CD28. This helps to signal the T-cell differentiation into a cytotoxic T-cell. [13] [16] The expression of CD80, as well as CD86, is increased by the presence of microbes and cytokines, which is the consequence of the presence of microbes. This mechanism ensures that costimulatory molecules for T-cells are present at the right time. [7]
CD80, often in tandem with CD86, plays a large and diverse role in regulating both the adaptive and the innate immune system. As mentioned above, this protein is crucial for immune cell activation in response to pathogens. The interaction of CD80 with CD28, together with TCR and MHC interaction, results in activation of nuclear factor‐κB (NF-ⲕB), mitogen‐activated protein kinase (MAPK), and the calcium‐calcineurin pathway. These changes initiate the production of numerous factors, cytokines, and chemokines by T-cells. Noteworthy is the production of interleukin 2 (IL-2) as well as ɑ-chain of CD25 (which is a receptor of IL-2), CD40 ligand, tumor necrosis factor‐α (TNFα), TNF‐β, and interferon‐γ (IFN‐γ). T-cells also increase the production of macrophage inflammatory proteins 1α and 1β (MIP‐α1 and MIP‐1β) and prevent apoptosis by induction of anti-apoptotic protein expression (e.g., Bcl‐X and Bcl‐2). [14] [17] [18] [19] [20] CD80 interaction with CD28 also further stimulates dendritic cells, enhancing cytokine production, specifically IL-6, a pro-inflammatory molecule. [21] [22] Neutrophils can also activate macrophages with CD80 via CD28. [22] Last but not least, the interaction of CD80 and CD28 enhances cell‐cycle progression by upregulating the expression levels of D‐cyclin. [14]
In contrast to the stimulatory interaction with CD28, CD80 also regulates the immune system through an inhibitory interaction with CTLA-4. Dendritic cells are suppressed by a CTLA-4-CD80 interaction, [22] and this interaction also promotes the suppressive effects of regulatory T cells, which can prevent an immune response to self-antigen. [18]
In addition to interactions with CD28 and CTLA-4, CD80 is also thought to interact with a separate ligand on Natural Killer cells, triggering the Natural Killer cell-mediated cell death of the CD80 carrier. [23] CD80 may also play a role in the negative regulation of effector and memory T-cells. If the interaction between an antigen-presenting cell and a T-cell is stable enough, the T-cell can remove the CD80 from the antigen-presenting cell. Under the right conditions, this transfer of the CD80 may induce T-cell apoptosis. [24] Finally, CD80 signaling on activated B-cells may regulate antibody secretion during infection. [25]
Another ligand of CD80 is programmed death-ligand 1 (PD‐L1), expressed on the surface of T-cells, B-cells, DCs, and macrophages. This interaction is inhibiting and causes a reduction in T-cell activation as well as reduction of cytokine production. Its dissociation constant with CD80 is between the CD28 and CTLA-40 (Kd = 1.4 μM). [14] [26]
The complicated role CD80 plays in immune system regulation presents an opportunity for CD80 interactions to go rogue in various diseases. The up-regulation of CD80 has been linked to various autoimmune diseases, including multiple sclerosis, [27] systemic lupus erythematosus [28] and sepsis [29] (which may partly be due to over-active T-cells), and CD80 has also been shown to help spread of HIV infection in the body. [30] CD80 is also linked to various cancers, though some experience CD80 induced tolerance via possible regulatory T-cell interaction. [31] Others experience inhibited growth and metastasis-related to CD80 up-regulation, [32] further exemplifies the complicated role CD80 plays.
The triggering of Natural Killer cell-mediated death via CD80 interactions has been explored as possible cancer immunotherapy by inducing CD80 expression on tumor cells. [23]
A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.
Cytotoxic T-lymphocyte associated protein 4, (CTLA-4) also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. It is encoded by the gene CTLA4 in humans.
B7 is a type of integral membrane protein found on activated antigen-presenting cells (APC) that, when paired with either a CD28 or CD152 (CTLA-4) surface protein on a T cell, can produce a costimulatory signal or a coinhibitory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell, respectively. Binding of the B7 of APC to CTLA-4 of T-cells causes inhibition of the activity of T-cells.
Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.
CD28 is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor (TCR) can provide a potent signal for the production of various interleukins.
In immunology, an immunological synapse is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T/B cell or Natural Killer cell. The interface was originally named after the neuronal synapse, with which it shares the main structural pattern. An immunological synapse consists of molecules involved in T cell activation, which compose typical patterns—activation clusters. Immunological synapses are the subject of much ongoing research.
Inducible T-cell costimulator is an immune checkpoint protein that in humans is encoded by the ICOS gene.
Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.
Abatacept, sold under the brand name Orencia, is a medication used to treat autoimmune diseases like rheumatoid arthritis, by interfering with the immune activity of T cells. It is a modified antibody.
Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.
ICOS ligand is a protein that in humans is encoded by the ICOSLG gene located at chromosome 21. ICOSLG has also been designated as CD275.
V-set domain-containing T-cell activation inhibitor 1 is a protein that in humans is encoded by the VTCN1 gene.
Programmed cell death 1 ligand 2 is a protein that in humans is encoded by the PDCD1LG2 gene. PDCD1LG2 has also been designated as CD273. PDCD1LG2 is an immune checkpoint receptor ligand which plays a role in negative regulation of the adaptive immune response. PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1).
Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.
Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.
CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily.
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