Optimal activation of T lymphocytes requires a carefully orchestrated interplay between two key signals. The first signal originates from the T cell receptor (TCR) recognizing a specific antigen. However, this initial encounter is insufficient on its own. A crucial "costimulatory" signal is needed for full T cell activation, delivered by the engagement of costimulatory receptors, such as CD28, on the T cell surface with their corresponding ligands on antigen-presenting cells (APCs) (Chen & Flies 2013, Acuto et al. 2003, Slavik et al. 1999).
The CD28 superfamily is central to costimulation, encompassing a diverse group of receptors including CD28, CTLA-4, ICOS, PD-1, and BTLA. These receptors have both positive and negative influences on T cell activation. CD28 and ICOS provide a positive boost, while CTLA-4, PD-1, and BTLA act as inhibitory brakes. CD28 and CTLA-4 bind to B7 family ligands CD80 (B7.1) and CD86 (B7.2), with CD28 delivering stimulatory signals and CTLA-4 providing inhibitory signals. ICOS interacts with ICOS ligand (ICOS-L), enhancing T cell activation and function. PD-1 binds to PD-L1 and PD-L2, mediating inhibitory signals that modulate the immune response. BTLA engages with HVEM (Herpesvirus entry mediator), transmitting inhibitory signals. This balance between stimulatory and inhibitory signals is essential, allowing the immune system to mount effective responses against pathogens while preventing the induction of T cell unresponsiveness and apoptosis (Chen & Flies 2013, Sharpe & Freeman 2002, Carreno & Collins 2002).
The expression of these receptors varies: CD28 is constantly present on naive T cells, whereas CTLA-4 expression depends on prior CD28 engagement. ICOS, PD-1, and BTLA are induced only after initial T cell stimulation. These variations in expression ensure precise regulation of T cell responses at different stages of activation (Sharpe & Freeman 2002). The receptors themselves also exhibit structural differences. CD28, CTLA-4, and ICOS share a single extracellular domain resembling an immunoglobulin molecule (IgV-like). In contrast, BTLA has a distinct structure with an IgC-like domain. Similarly, the costimulatory ligands, such as B7-1 and B7-2, have unique structural features that enable specific interactions with their partner receptors.