3. Novel Co-Stimulatory Molecules
Co-stimulatory molecules are a diverse group of proteins expressed on the surface of antigen-presenting cells (APCs) and other cells involved in immune responses. They play a crucial role in amplifying or reducing (Secondary signals ), the initial activation signals delivered to T cells by the T cell receptor (TCR) following its interaction with an antigen/major histocompatibility complex (MHC), thereby influencing T cell differentiation and outcome. [268, 269]. Hence, co-stimulatory molecules provide secondary signals to T cells in addition to the primary signal delivered through the T cell receptor (TCR) interaction with antigen-presenting molecules (e.g., MHC molecules).
The primary function of co-stimulatory molecules is to ensure that T cell activation occurs appropriately in response to pathogens or other stimuli (Figure 2). Without adequate co-stimulation, T cells may become tolerant or undergo apoptosis (cell death) instead of becoming activated and mounting an immune response [268, 270] Traditionally, the best-known co-stimulatory molecules belong to the CD28 family, such as CD80 (B7-1) and CD86 (B7-2), which interact with CD28 on T cells to promote activation [268, 271].
However, ongoing research has identified several novel co-stimulatory molecules that expand our understanding of immune regulation and offer new opportunities for therapeutic interventions (Figure 2). These novel co-stimulatory molecules can be classified into different families based on their structural and functional characteristics. For example, members of the TNF receptor superfamily (e.g., OX40, 4-1BB) and the TNF ligand superfamily (e.g., CD40, CD27) have emerged as important regulators of T cell responses [268, 271, 272] Other families include adhesion molecules (e.g., ICOS, LFA-1) and receptors involved in cytokine signaling (e.g., IL-2R, IL-7R) [273, 274]. These co-stimulatory molecules are mainly categorized into two groups: the immunoglobulin superfamily (IgSF) include CD28, inducible co-stimulator (ICOS) and CD226. and the tumor necrosis factor receptor superfamily (TNFRSF) including OX40 receptor (CD134; TNFRSF4), CD27, 4-1BB (CD137; TNFRSF9), and glucocorticoid-induced TNFR-related (GITR) protein (CD357; TNFRSF18), death receptor 3 and CD40) [275, 276]. Additionally,cell adhesion molecules including CD2 and LFA-1 (Lymphocyte Function-Associated Antigen 1) act as co-stimulatory molecules [277].
The roles of these co-stimulatory molecules vary widely. Some enhance T cell activation and effector functions, promoting immune responses against infections and tumors. Others regulate immune tolerance and prevent excessive immune activation, thereby maintaining immune homeostasis and preventing autoimmune diseases [268].