<unk>  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.<unk>  has a crucial role in modulatating T-cell immune function as a checkpoint protein at the immunological synapse.<unk>  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. Interaction of<unk>  with CD28 triggers costimulatory signals and results in enhanced and sustained T-cell activation. In contrast, contrary interaction of<unk>  with CTLAT-4 inhibits parts of T-cell effector function. These two ligands are structurally homologous, and they compete with each other for binding sites. However, the bond with CTLA-4 has up to 2500 fold higher avidity than with CD28. This illustrates that inhibitory interaction with CTLA-4 is predominant.<unk>  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. 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. When stimulated by<unk> , T helper cells preferentially differentiate into Th1 cells.<unk>  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,<unk>  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. The expression of<unk> , 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.<unk> , 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<unk>  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).<unk>  interaction with CD28 also further stimulates dendritic cells, enhancing cytokine production, specifically IL-6, a pro-inflammatory molecule. Neutrophils can also activate macrophages with<unk>  via CD28. Last but not least, the interaction of<unk>  and CD28 enhances cell‐cycle progression by upregulating the expression levels of D‐cyclin. In contrast to the stimulatory interaction with CD28,<unk>  also regulates the immune system through an inhibitory interaction with CTLA-4. Dendritic cells are suppressed by a CTLA-4-CD80 interaction, and this interaction also promotes the suppressive effects of regulatory T cells, which can prevent an immune response to self-antigen. In addition to interactions with CD28 and CTLA-4,<unk>  is also thought to interact with a separate ligand on Natural Killer cells, triggering the Natural Killer cell-mediated cell death of the<unk>  carrier.<unk>  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<unk>  from the antigen-presenting cell. Under the right conditions, this transfer of the<unk>  may induce T-cell apoptosis. Finally,<unk>  signaling on activated B-cells may regulate antibody secretion during infection. Another ligand of<unk>  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<unk>  is between the CD28 and CTLA-40 (Kd = 1.4 μM).
CD80
CD74
CD86
CD23
CD137
CD22
CD4
CD44