Role of Interleukin-15 (IL-15) in the Immune System
IL-15 is a critical pleiotropic cytokine that promotes survival, proliferation, and activation of natural killer (NK) cells, CD8+ T cells, and NKT cells, with emerging therapeutic applications in sepsis, vaccine enhancement, cancer immunotherapy, and autoimmune disease, though its role in autoimmunity remains complex and context-dependent. 1, 2, 3
Core Immunological Functions
Cellular Targets and Effects
IL-15 exerts its primary effects on multiple lymphocyte populations through distinct receptor signaling mechanisms:
- NK cells: IL-15 is essential for NK cell development, homeostasis, function, and survival, making it critical for innate immunity 3, 4
- CD8+ T cells: IL-15 promotes survival, proliferation, and activation of CD8+ memory T cells, particularly through telomerase activation 2, 4
- NKT-like cells: IL-15 increases proliferative capacity and telomerase expression in CD56+CD3+ NKT-like cells by up to 2.5-fold 2
- Neutrophils and macrophages: IL-15 promotes activation of these innate immune cells and is critical to dendritic cell (DC) function 4
Signaling Mechanisms
IL-15 utilizes three distinct receptor chains and activates multiple signaling pathways more potently than IL-2 2, 5:
- JAK-STAT pathway: Important for telomerase upregulation in NK and NKT cells 2
- PI3K-AKT pathway: Critical for telomerase expression in NK and NKT cells 2
- Ras-MAPK pathway: Involved specifically in CD8+ T cell telomerase expression 2
IL-15 demonstrates superior proliferative effects compared to IL-2 at both low and high doses, with more potent activation of immune-enhancing signaling cascades 2, 5
Clinical Applications and Therapeutic Potential
Sepsis and Critical Illness
In sepsis, IL-15 prevents apoptosis, reverses both innate and adaptive immune dysfunction, and improves survival 1:
- IL-15 prevents neutrophil apoptosis through upregulation of anti-apoptotic Mcl-1 protein and activation of Janus kinase-2, p38 MAPK, and ERK-1/2 pathways 1
- Myeloid DCs that produce IL-15 (along with IL-12) become progressively impaired as circulating tumor burden or sepsis severity increases 1
- In Sézary syndrome, declining DC production of IL-15 correlates with progressive immune dysfunction and increased susceptibility to opportunistic infections 1
Vaccine Enhancement
IL-15 increases vaccine efficacy through mechanisms linked to dendritic cell maturation and enhanced antibody titers 1:
- Subcutaneous immunization combining modified vaccinia Ankara (MVA) with IL-15 induced both humoral and cellular responses, with antibody responses fourfold higher than MVA alone 1
- This vaccine-cytokine combination represents a promising approach for enhancing protective immunity 1
Cancer Immunotherapy
IL-15 is being investigated for adoptive cell therapy expansion and as an immune-enhancing agent 2, 5:
- IL-15 potently stimulates telomerase upregulation in NK, NKT, and CD8+ T cells, making it valuable for ex vivo expansion of these populations for adoptive transfer 2
- IL-15 signaling activates proto-oncogenes and has been implicated in leukemia of large granular lymphocytes, cutaneous T-cell lymphoma, and multiple myeloma 5
- Therapeutic strategies include both IL-15-mediated enhancement of anti-tumor immunity and disruption of aberrant IL-15 signaling in IL-15-driven malignancies 5
Autoimmune Disease
The role of IL-15 in autoimmunity is complex and disease-specific 6:
- IL-15 has been implicated in rheumatoid arthritis, autoimmune diabetes, inflammatory bowel disease, celiac disease, and psoriasis 6
- Pre-clinical models demonstrate beneficial effects of targeting IL-15 signaling in autoimmunity 6
- However, unlike therapies targeting other cytokines, anti-IL-15 therapies have not yet been successful in human autoimmune disease trials 6
Important Caveats and Clinical Considerations
Context-Dependent Effects
- IL-15 deficiency in sepsis and immunodeficiency states warrants supplementation, whereas IL-15 blockade may be appropriate in certain autoimmune conditions and IL-15-driven malignancies 1, 5, 6
- In Sézary syndrome, declining myeloid DC production of IL-15 contributes to progressive immune dysfunction, NK cell impairment, and increased severity of opportunistic infections 1
Comparison with IL-2
IL-15 demonstrates several advantages over IL-2 for immunotherapy 2, 3:
- IL-15 affects a wider range of target cell populations than IL-2 3
- IL-15 utilizes different signaling mechanisms and demonstrates superior proliferative effects at equivalent doses 2, 3
- IL-15 increases telomerase expression and cellular expansion more effectively than IL-2, particularly at low doses 2
Trans-Presentation Mechanism
IL-15 uses a unique signaling pathway whereby IL-15 associates with IL-15Rα during biosynthesis, and this complex is "trans-presented" to responder cells expressing the IL-2/15Rβγc receptor complex 6. This mechanism distinguishes IL-15 from other cytokines and may explain both its potency and the challenges in therapeutic targeting 6.