Cluster of Differentiation 28 (CD28) and Tumor necrosis factor receptor superfamily member 9 (4-1BB) (CD28/4-1BB)

CD28 and 4-1BB (CD137) are pivotal costimulatory receptors that regulate T-cell activation, metabolism, and survival [1.1.1, 1.2.2]. CD28, a member of the immunoglobulin superfamily, provides a potent 'signal 2' that lowers the threshold for T-cell receptor (TCR) activation and drives rapid proliferation through the PI3K/Akt pathway [1.1.1, 1.2.4]. In contrast, 4-1BB is a member of the tumor necrosis factor receptor (TNFR) superfamily that is upregulated following activation and promotes long-term persistence and memory formation via TRAF-mediated signaling [1.2.2, 1.4.1]. These molecules are the primary costimulatory domains utilized in second-generation chimeric antigen receptor (CAR) T-cell therapies, where they dictate the metabolic and functional fate of the engineered cells [1.3.1, 1.3.4]. CD28-based CARs, such as axicabtagene ciloleucel, are characterized by rapid effector responses and high glycolytic flux, whereas 4-1BB-based CARs, such as tisagenlecleucel, favor oxidative phosphorylation and enhanced durability in vivo [1.3.3, 1.3.5]. Beyond CAR-T cells, these receptors are targets for agonist antibodies like urelumab in cancer immunotherapy and are being explored for their roles in autoimmune and inflammatory diseases [1.2.2, 1.4.1]. The choice between these domains is a critical design parameter in synthetic immunology, balancing the need for immediate potency against the requirement for sustained antitumor surveillance. Safety concerns associated with these targets include cytokine release syndrome and neurotoxicity, which are often more pronounced with CD28-mediated signaling [1.3.1, 1.2.3].

Other names

CD284-1BBCD137TNFRSF9Tp44ILAInduced by Lymphocyte ActivationT-cell costimulatory receptors

Agonism of T-cell costimulatory signaling. CD28 domains in CAR-T cells activate PI3K/Akt and NF-kB pathways to drive rapid expansion and effector function. 4-1BB domains recruit TRAF1/2/3 to activate NF-kB and MAPK pathways, promoting mitochondrial biogenesis and T-cell persistence.