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].