Interleukin-15 receptor complex on gamma-delta T cells (IL-15R on γδ T cells)

The Interleukin-15 (IL-15) receptor complex on gamma-delta (γδ) T cells is a multi-subunit signaling apparatus essential for the development, homeostasis, and effector function of this unique T cell lineage (PNAS, 2015). It typically consists of the high-affinity IL-15 receptor alpha (IL-15RA) subunit, the IL-2 receptor beta (IL-2RB/CD122) subunit, and the common cytokine receptor gamma (IL-2RG/CD132) subunit (Frontiers in Immunology, 2020). On γδ T cells, IL-15 signaling promotes rapid proliferation, enhances cytotoxic activity through the upregulation of granzymes and perforin, and stimulates the production of pro-inflammatory cytokines such as interferon-gamma (IFN-γ) (Journal of Hematology & Oncology, 2016). This receptor complex is a critical target in cancer immunotherapy, where IL-15 agonists are used to expand γδ T cells and improve their anti-tumor efficacy against both hematological and solid malignancies (NIH, 2022). Additionally, the receptor plays a role in the maintenance of tissue-resident γδ T cells, which provide a first line of defense at mucosal surfaces (Nature Reviews Immunology, 2015). Dysregulation of IL-15 receptor signaling is also implicated in inflammatory and autoimmune diseases, such as celiac disease, where it can drive tissue destruction (NIH, 2015). Therapeutic agents like Nogapendekin alfa inbakicept (N-803) specifically target this complex to harness the innate-like killing potential of γδ T cells (FDA, 2024).

Other names

IL-15 receptorIL-15RCD122/CD132/IL-15RA complexInterleukin-15 receptor complexIL-15R on gamma-delta T cells

The mechanism of action involves the binding of IL-15 or its mimetics to the heterotrimeric IL-15 receptor complex, which triggers the activation of Janus kinases (JAK1 and JAK3) and subsequent phosphorylation of Signal Transducer and Activator of Transcription (STAT5 and STAT3) proteins (NIH, 2023). This signaling cascade, along with the activation of the PI3K/Akt and MAPK/ERK pathways, drives the transcription of genes involved in cell cycle progression, survival (e.g., Mcl-1), and cytotoxic effector functions (e.g., Granzyme B and Perforin) in gamma-delta T cells (Frontiers in Immunology, 2020).