CD28 is a critical costimulatory receptor expressed on the surface of T cells, playing a pivotal role in T cell activation, proliferation, and differentiation. It is a type I transmembrane glycoprotein that forms homodimers and interacts with its ligands CD80 (B7-1) and CD86 (B7-2), which are primarily found on antigen-presenting cells. The engagement of CD28 with these ligands provides a secondary signal necessary for full T cell activation, which complements the primary signal generated by the T cell receptor (TCR) engagement with the antigen-presenting MHC molecule. This costimulation is essential for preventing T cell anergy and inducing robust immune responses. CD28 signaling activates various downstream pathways, including the PI3K-AKT pathway, which is important for cell survival and metabolism. It also upregulates the expression of IL-2 and its receptor, leading to T cell proliferation. Furthermore, CD28 has been implicated in the generation and maintenance of regulatory T cells (Tregs), and its expression levels can vary in different T cell subsets, including a decrease in expression on highly differentiated effector T cells. The importance of CD28 in immune responses is underscored by the immune defects observed in CD28-deficient mice, which include impaired T cell help for B cells and poor memory T cell responses.