The subunits of IL-12, originating from two distinct cells, can functionally synergize to protect against pathogen dissemination in vivo.
The subunits of IL-12, originating from two distinct cells, can functionally synergize to protect against pathogen dissemination in vivo.
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DOI：
10.1016/j.celrep.2021.109816
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发表时间：
2021-10-12
期刊：
影响因子：
8.8
通讯作者：
Singh NJ
中科院分区：
文献类型：
--
作者：
Gerber AN;Abdi K;Singh NJ
细胞因子通常是单基因产物，除了异源二聚体白细胞介素（IL）-12家族。已知原型IL-12的两个亚基（IL-12 p40和IL-12 p35）在活化的骨髓细胞中同时共表达，所述骨髓细胞分泌完全活性的异源二聚体以促进先天性和适应性细胞中的干扰素（IFN）γ产生。我们发现，含有只能表达IL-12 p40或IL-12 p35但不能同时表达两者的细胞混合物的嵌合小鼠产生功能性IL-12。这种交替的两细胞途径需要来自造血细胞的IL-12 p40与来自辐射抗性细胞的IL-12 p35在细胞外缔合。双细胞机制足以推动初始感染远端部位的局部T细胞分化，并有助于控制感染部位病原体的全身传播，尽管不是寄生虫负荷。广泛地说，这表明在感染部位的前哨细胞的IL-12 p40单体的早期分泌可能有助于为潜在的病原体到达准备远端宿主组织。先天性细胞因子IL-12是IFNγ产生的关键增强剂。Gerber等人表明，IL-12活性可由体内两种不同的细胞独立地贡献IL-12的不同亚基而产生。这种协同的双细胞IL-12可以限制病原体传播到远离原发感染部位的组织。
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. The innate cytokine IL-12 is a critical enhancer of IFNγ production. Gerber et al. show that IL-12 activity can result from two distinct cells contributing different subunits of IL-12 independently, in vivo. This collaborative, two-cell version of IL-12 could limit pathogen dissemination to tissues distant from the primary infection site.
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影响因子：
6.7
作者：
Hurdayal R;Nieuwenhuizen NE;Revaz-Breton M;Smith L;Hoving JC;Parihar SP;Reizis B;Brombacher F
通讯作者：
Brombacher F
影响因子：
15.3
作者：
D'Andrea, A;Aste-Amezaga, M;Valiante, N M;Ma, X;Kubin, M;Trinchieri, G
通讯作者：
Trinchieri, G
DOI：
10.1084/jem.169.1.59
发表时间：
1989-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Heinzel FP;Sadick MD;Holaday BJ;Coffman RL;Locksley RM
通讯作者：
Locksley RM
DOI：
10.1073/pnas.0802331105
发表时间：
2008-07-22
影响因子：
11.1
作者：
Kimblin, Nicola;Peters, Nathan;Sacks, David
通讯作者：
Sacks, David
影响因子：
4.8
作者：
Jalah, Rashmi;Rosati, Margherita;Felber, Barbara K.
通讯作者：
Felber, Barbara K.