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

概述：IL-12家族异源二聚体调节T细胞产生IL-4 免疫系统调整效应器应答以匹配特定病原体以及免疫原。 它们感染的组织。在这种情况下，由先天性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的作用。IL-12驱动T细胞向IFNγ分化 产生效应物，而IL-23促进IL-17应答。IL-12和IL-23都是异源二聚体 它们共享一个共同的亚基（IL-12 p40），但在第二亚基（IL-12和IL-12的IL-12 p35）上不同。 IL-23的23 p19）。这一建议的意义在于，我们确定了一种新的先天性细胞因子， 家族，其促进产生IL-4和IL-10的T细胞的分化。这个新 异源二聚体细胞因子也使用IL-12 p40亚基，但与另一种不同的配偶体结合 蛋白质，一种分泌的CD 5样抗原，称为CD 5L。在本建议中，我们将研究 P40+ CD 5L发挥其IL-4/IL-10促进活性的机制，使用新的重组 蛋白质，专门开发的单克隆抗体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“异二聚体 由IL-12 p40加CD 5L形成的CD 5L作为先天性细胞因子发挥作用，并扩增IL-4和IL-10 通过体内淋巴细胞产生”。在具体的目标1中，我们描述了不同的血统， 免疫细胞（包括T、B、NKT、ILC、巨噬细胞等）其在体内对P40+ CD 5L应答。 然后，我们将评估参与感受P40+ CD 5L的细胞受体和主要的 在活化的T细胞中这些受体下游的信号传导途径。最后，我们将表演 无偏转录组学分析以鉴定P40+ CD 5L的总体影响。第二个目标， 我们将使用感染和肿瘤模型，利用不同组织中P40+ CD 5L水平的自然变化， 小鼠品系，以确定其在IL 4和IL 10发挥关键作用的两种情况下的作用。对 完成这些研究后，我们希望一种新的先天性细胞因子的报告能引起研究人员的兴趣。 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。未来的研究也将有助于将P40-CD 5L的生物学纳入到细胞内。 网络的其他IL-12家族细胞因子，并发展更完整的了解先天性- 免疫系统中的自适应通信。

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.