The Cluster of differentiation 80 (alsoCD80 andB7-1) is a B7, type I membrane protein[5] in theimmunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related toCD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact withcostimulatory receptorsCD28,CTLA-4 (CD152) and the p75 neurotrophin receptor.[6][7]
CD80 is a member of theB7 family, which consists of molecules present atAPCs and their receptors present on theT-cells.[7] CD80 is present specifically onDC, activatedB-cells, andmacrophages, but alsoT-cells.[7][8] CD80 is also atransmembraneglycoprotein and a member of theIg superfamily.[7] It is composed of 288amino acids, and its mass is 33kDa.[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 bothmonomers ordimers, but predominantly dimers.[7][10][11] These two forms exist in dynamicequilibrium.[12]
CD80 shares 25% of sequences withCD86; however, CD80 has a ten-fold higheraffinity forCD28 andCTLA-4 thanCD86. Moreover, CD80 interacts with its ligand with faster binding kinetics and slower dissociation constants thanCD86. Both human CD80 and CD86 are located atchromosome 3; the exact region is 3q13.3-q21.[7]
Human andmurine 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 variousimmune cells, includingB-cells,monocytes, or T-cells, but most typically atantigen-presenting cells (APCs) such asdendritic cells.[6][7][13] CD80 has a crucial role in modulating T-cell immune function as a checkpoint protein at theimmunological synapse.[14]
CD80 is the ligand for the proteinsCD28 (for autoregulation and intercellular association) andCTLA-4 (for attenuation of regulation and cellular disassociation) found on the surface ofT-cells.[6][13] Interaction of CD80 with CD28 triggerscostimulatory 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 twoligands are structurally homologous, and they compete with each other forbinding sites.[14] However, the bond with CTLA-4 has up to 2500 fold higheravidity than with CD28.[7] This illustrates that inhibitory interaction with CTLA-4 is predominant.[14]
CD80 binds toCD28 andCTLA-4 with loweraffinity 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 theimmunological synapse betweenantigen-presenting cells,B-cells,dendritic cells andT-cells that result in T and B-cell activation, proliferation and differentiation.[11]
When stimulated by CD80,T helper cells preferentially differentiate intoTh1 cells.[11] CD80 is an essential component indendritic cell licensing andcytotoxic T-cell activation. When the major histocompatibility complex class II (MHC class II)-peptide complex on adendritic cell interacts with the receptor on aT helper cell, CD80 is up-regulated, licensing thedendritic cell and allowing for interaction between thedendritic cell andCD 8+ T-cells viaCD28. This helps to signal the T-cell differentiation into acytotoxic T-cell.[13][16] The expression of CD80, as well asCD86, is increased by the presence ofmicrobes andcytokines, which is the consequence of the presence of microbes. This mechanism ensures that costimulatory molecules forT-cells are present at the right time.[7]
CD80, often in tandem withCD86, plays a large and diverse role in regulating both theadaptive and theinnate immune system. As mentioned above, this protein is crucial for immune cell activation in response topathogens. The interaction of CD80 with CD28, together withTCR andMHC 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, andchemokines by T-cells. Noteworthy is the production of interleukin 2 (IL-2) as well as ɑ-chain ofCD25 (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 ofmacrophage inflammatory proteins 1α and 1β (MIP-α1 and MIP-1β) and preventapoptosis by induction of anti-apoptotic protein expression (e.g.,Bcl-X andBcl-2).[14][17][18][19][20] CD80 interaction withCD28 also further stimulatesdendritic cells, enhancingcytokine production, specificallyIL-6, a pro-inflammatory molecule.[21][22]Neutrophils can also activatemacrophages with CD80 viaCD28.[22] Last but not least, the interaction of CD80 and CD28 enhances cell-cycle progression by upregulating the expression levels ofD-cyclin.[14]
In contrast to the stimulatory interaction withCD28, CD80 also regulates the immune system through an inhibitory interaction withCTLA-4.Dendritic cells are suppressed by a CTLA-4-CD80 interaction,[22] and this interaction also promotes the suppressive effects ofregulatory T cells, which can prevent an immune response toself-antigen.[18]
In addition to interactions withCD28 andCTLA-4, CD80 is also thought to interact with a separate ligand onNatural 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 anantigen-presenting cell and aT-cell is stable enough, the T-cell can remove the CD80 from the antigen-presenting cell by a mechanism dubbedtrans-endocytosis. Under the right conditions, this transfer of the CD80 may induce T-cellapoptosis.[24] Finally, CD80 signaling on activatedB-cells may regulate antibody secretion duringinfection.[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 variousautoimmune diseases, includingmultiple sclerosis,[27]systemic lupus erythematosus[28] andsepsis[29] (which may partly be due to over-active T-cells), and CD80 has also been shown to help spread ofHIV infection in the body.[30] CD80 is also linked to variouscancers, though some experience CD80 induced tolerance via possibleregulatory T-cell interaction.[31] Others experience inhibited growth andmetastasis-related to CD80 up-regulation,[32] further exemplifies the complicated role CD80 plays.
The triggering ofNatural Killer cell-mediated death via CD80 interactions has been explored as possible cancerimmunotherapy by inducing CD80 expression on tumor cells.[23]
