An IL-12 family heterodimer that regulates IL-4 production by T cells

综述：调节T细胞产生IL-4的IL-12家族异源二聚体 免疫系统调整效应器的反应以匹配特定的病原体以及 它们感染的组织。在这种情况下，天然细胞产生的一对细胞因子(IL-12和IL-23) 在感染的早期起着重要作用。IL-12促进T细胞向干扰素γ分化 产生效应器，而IL-23促进IL-17反应。IL-12和IL-23都是异源二聚体 它们共享一个共同的亚基(IL-12p40)，但在第二个亚基(IL-12和IL-12的IL-12p35)上不同 23p19为IL-23)。这一提议的意义在于，我们在这个过程中发现了一种新的天生细胞因子 促进产生IL-4和IL-10的T细胞的分化。这是一项新的 异源二聚体细胞因子也使用IL-12p40亚单位，但结合了不同的伴侣 蛋白质，一种分泌的类似CD5的抗原，称为CD5L。在这项建议中，我们将研究 P40 CD5L促进IL-4/IL-10活性的机制 蛋白质，特别开发了单抗和可用的基因敲除小鼠。 因此，以下具体目标将评估我们的中心假设，即“一种异源二聚体 IL-12p40+CD5L作为天然细胞因子发挥作用，放大IL-4和IL-10 在体内由淋巴细胞产生“。在具体目标1中，我们描述了不同的血统 免疫细胞(包括T、B、NKT、ILCs、巨噬细胞等)它们在体内对P40 CD5L有反应。 然后我们将评估参与感知P40 CD5L和主要 在激活的T细胞中，这些受体下游的信号通路。最后，我们将表演 无偏见的转录分析，以确定P40 CD5L的全球影响。在第二个目标中， 我们将使用感染和肿瘤模型，利用不同组织中P40 CD5L水平的自然变化 白介素4和白介素10在两种情况下扮演关键角色。在……上面 随着这些研究的完成，我们预计一种新的先天细胞因子的报告将对 更广泛的社区以及使用我们的试剂开发新的免疫疗法 已经发展起来了。未来的研究还将有助于将P40-CD5L的生物学结合到 网络的其他IL-12家族的细胞因子和发展更全面的理解先天的- 免疫系统中的适应性交流。

Summary: An IL-12 family heterodimer that regulates IL-4 production by T cells The immune system tailors effector responses to match both specific pathogens as well as the tissues they infect. In this context, a pair of cytokines (IL-12 and IL-23) produced by innate cells early in an infection play an important role. IL-12 drives the differentiation of T cells towards IFNγ producing effectors while IL-23 promotes IL-17 responses. Both IL-12 and IL-23 are heterodimers which share a common subunit (IL-12p40) but differ in the 2nd subunit (IL-12p35 for IL-12 and IL- 23p19 for IL-23). The significance of this proposal is that we identify a new innate cytokine in this family, which promotes the differentiation of IL-4 and IL-10 producing T cells. This new heterodimeric cytokine also uses the IL-12p40 subunit, but binds a distinct partner from the other proteins, a secreted CD5-like antigen called CD5L. In this proposal, we will examine the mechanisms by which P40+CD5L exerts its IL-4/IL-10 promoting activity, using new recombinant proteins, specifically developed monoclonal antibodies and available knockout mice. Accordingly, the following specific aims will evaluate our central hypothesis that “A heterodimer formed by IL-12p40 plus CD5L functions as an innate cytokine and amplifies IL-4 and IL-10 production by lymphocytes in vivo”. In specific aim 1 we characterize the different lineages of immune cells (including T, B, NKT, ILCs, macrophages, etc.) which respond to P40+CD5L in vivo. We will then evaluate the cellular receptors involved in sensing P40+CD5L and the major signaling pathways downstream of these receptors in activated T cells. Finally, we will perform unbiased transcriptomic analysis to identify the global impact of P40+CD5L. In the second aim, we will use infection and tumor models, exploiting natural variation of P40+CD5L levels in different mouse strains to pinpoint its role in two contexts where the IL4 and IL10 play critical roles. On completion, of these studies we expect the report of a new innate cytokine to be of interest to the broader community as well as the development of new immunotherapies using the reagents we have developed. Future studies will also help incorporate the biology of P40-CD5L into the network of other IL-12 family cytokines and develop a more complete understanding of innate- adaptive communication in the immune system.