TNFRSF9/4-1BB/CD137

TNFRSF9/4-1BB/CD137 is a TNF receptor superfamily member that provides costimulatory signals for activated T cells and mediates growth and survival signals for T cells^[1]. Mechanistically, 4-1BB functions with TCR/CD3 stimulation and activates JNK signaling in T cells^[2]. This pathway supports activated CD8⁺ T-cell costimulation, cytotoxic responses, and memory T-cell formation, while CD137 signaling can also activate NK cells and dendritic cells^[3]. In monocytes, CD137 induces IL-8 and TNF-α production, inhibits IL-10 expression, and links CD137 biology to innate immune activation^[4]. In disease models, TNFRSF9 variation affects type 1 diabetes susceptibility, and 4-1BB costimulation changes IL-2 production and T-cell proliferation in NOD congenic mice^[1]. In lichen planus, CXCL13⁺CD8⁺ T cells express TNFRSF9, which enhances cytotoxic responses in skin^[5]. Compared with membrane-bound CD137, soluble CD137 is generated by alternative splicing, released by activated lymphocytes, and detected at increased levels in rheumatoid arthritis sera^[6]. For research applications, agonistic anti-4-1BB antibody directly stimulates peptide-specific CD8⁺ T cells and supports long-lasting CD8 memory in vaccination models^[7].