Lanzar Zachary R, Aldridge Daniel L, Jayaraman Bhargavi, Haskins Breanne, Howard Christian A, Arana Kathya, Bunkofske Molly E, Mulka Kathleen, Pardy Ryan D, Byerly Jessica, Striepen Boris, Lupardus Patrick, Hunter Christopher A
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Synthekine, 1505 O'Brien Drive, Menlo Park, CA 94025, USA.
Cell Rep. 2025 Jun 24;44(6):115840. doi: 10.1016/j.celrep.2025.115840. Epub 2025 Jun 12.
Interleukin-12 (IL-12) stimulates natural killer (NK) and T cell production of interferon gamma (IFN-γ), but adverse events from NK cell activation have limited its clinical use. This study shows the impact of half-life-extended, full (IL-12Fc) and partial (IL-12 3x AlaFc) IL-12 agonists on the immune system. In naive mice, serial treatment with IL-12Fc induces systemic IFN-γ, multi-organ pathology, and alterations in myelopoiesis. IL-12 Fc stimulates NK cell production of IFN-γ but also activates CD4, CD8 T, and NKT cells. IL-12 Fc's ability to enhance the production of IFN-γ facilitates myelopoiesis, but IFN-γ is not required for the development of systemic toxicity. In contrast, IL-12 3x Ala Fc avoids overt disease, activates CD4 and CD8 T cells, and induces myelopoiesis. These differential activities were harnessed to enhance resistance to infection, indicating that a threshold of IL-12 signaling is tolerated under steady-state conditions and that fine-tuning IL-12 agonism can bolster resistance without triggering pathology.
白细胞介素-12（IL-12）可刺激自然杀伤（NK）细胞和T细胞产生γ干扰素（IFN-γ），但NK细胞激活引发的不良事件限制了其临床应用。本研究展示了半衰期延长的全长（IL-12Fc）和部分（IL-12 3x AlaFc）IL-12激动剂对免疫系统的影响。在未接触过抗原的小鼠中，用IL-12Fc进行连续治疗会诱导全身性IFN-γ、多器官病变以及骨髓生成的改变。IL-12 Fc刺激NK细胞产生IFN-γ，但也会激活CD4、CD8 T细胞和NKT细胞。IL-12 Fc增强IFN-γ产生的能力促进了骨髓生成，但全身性毒性的发展并不需要IFN-γ。相比之下，IL-12 3x Ala Fc可避免明显疾病，激活CD4和CD8 T细胞，并诱导骨髓生成。利用这些不同的活性来增强抗感染能力，这表明在稳态条件下可耐受一定阈值的IL-12信号传导，并且微调IL-12激动作用可增强抵抗力而不引发病变。
