Cluster of differentiation 28 (CD28) is a member of the immunoglobulin superfamily representing a type I transmembrane glycoprotein and is constitutively expressed on the surface of more than 80 % CD4+ T cells and 50 % CD8+ T cells in humans, whereas in mice, all naïve T cells express CD28. As co-stimulatory receptor, CD28 interacts with its ligands, CD80 (B7-1) and CD86 (B7-2), which are expressed on antigen-presenting cells (APCs), such as dendritic cells, macrophages and B cells. This interaction provides a second signal, next to antigen recognition, that is inevitable for T cell activation and proliferation and consequently, for the initiation of effective adaptive immune responses. Engagement of CD28 induces intracellular signaling pathways leading to the activation of transcription factors and the expression of genes, which are involved in T cell activation, proliferation, and cytokine production. Particularly, CD28 signaling promotes the production of interleukin-2 (IL-2), a cytokine that is crucial for T cell proliferation, differentiation and survival. Furthermore, CD28 activation is involved in the generation of memory T cells, which contribute to sustained immunity. Aberrant CD28 signaling leads to autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Therapeutically, CD28 holds promise as target for immunomodulatory strategies, such as blocking CD28 co-stimulation in order to suppress excessive immune responses, which occur in autoimmune diseases and transplant rejection. Additionally, modulation of CD28 signaling is explored to enhance anti-tumor immune responses.
