Department of Microbiology & Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, HSF1, Room 380, Baltimore, MD 21201, USA.
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20850, USA.
Cell Rep. 2021 Oct 12;37(2):109816. doi: 10.1016/j.celrep.2021.109816.
Cytokines are typically single gene products, except for the heterodimeric interleukin (IL)-12 family. The two subunits (IL-12p40 and IL-12p35) of the prototype IL-12 are known to be simultaneously co-expressed in activated myeloid cells, which secrete the fully active heterodimer to promote interferon (IFN)γ production in innate and adaptive cells. We find that chimeric mice containing mixtures of cells that can only express either IL-12p40 or IL-12p35, but not both together, generate functional IL-12. This alternate two-cell pathway requires IL-12p40 from hematopoietic cells to extracellularly associate with IL-12p35 from radiation-resistant cells. The two-cell mechanism is sufficient to propel local T cell differentiation in sites distal to the initial infection and helps control systemic dissemination of a pathogen, although not parasite burden, at the site of infection. Broadly, this suggests that early secretion of IL-12p40 monomers by sentinel cells at the infection site may help prepare distal host tissues for potential pathogen arrival.
细胞因子通常是单基因产物，除了异二聚体白细胞介素 (IL)-12 家族。原型 IL-12 的两个亚基 (IL-12p40 和 IL-12p35) 已知在激活的髓样细胞中同时共表达，这些细胞分泌完全活性的异二聚体，以促进先天和适应性细胞中干扰素 (IFN)γ 的产生。我们发现，包含只能表达 IL-12p40 或 IL-12p35 但不能同时表达两者的细胞混合物的嵌合小鼠会产生功能性 IL-12。这种替代的两细胞途径需要来自造血细胞的 IL-12p40 与来自辐射抗性细胞的 IL-12p35 在外周缔合。两细胞机制足以推动初始感染部位以外的局部 T 细胞分化，并有助于控制感染部位病原体的全身传播，尽管不能控制寄生虫负担。广义地说，这表明感染部位的哨细胞早期分泌 IL-12p40 单体可能有助于为潜在的病原体到达准备远端宿主组织。
