An extrafollicular pathway for the generation of effector CD8(+) T cells driven by the proinflammatory cytokine, IL-12.
An extrafollicular pathway for the generation of effector CD8(+) T cells driven by the proinflammatory cytokine, IL-12.
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作者：
Shah S;Grotenbreg GM;Rivera A;Yap GS
促炎细胞因子IL-12驱动最终分化的KLRG1+效应CD8+ T细胞的产生。利用弓形虫疫苗模型，我们描述了naïve CD8+ T细胞成为末端效应器的事件序列以及由IL-12控制的分化步骤。我们证明，CD8+ T细胞上的直接IL-12信号传导对于诱导KLRG1和IFN-γ至关重要，但随后的CXCR3下调是由IL-12通过IFN-γ和IFN-γ诱导的趋化因子间接控制的。新生效应物的分化发生在滤泡外脾腔室，由不同于经典CD8α+ DC的DC晚期IL-12产生驱动。出乎意料的是，我们还发现KLRG1−和KLRG1+ CD8+ T细胞在边缘区和红髓区广泛增殖，这种增殖在KLRG1Hi CXCR3Lo最终阶段之前停止。我们的发现强调了效应T细胞产生的滤泡外途径的概念。DOI: http://dx.doi.org/10.7554/eLife.09017.001免疫系统有助于保护我们免受癌症、微生物感染和其他疾病的侵害。有几种不同类型的免疫细胞，每种都有特定的作用。例如，细胞毒性T细胞可以杀死体内受损或感染的其他细胞。这些细胞分布在身体的各个部位，包括脾脏的一个被称为白浆的区域，在那里它们处于不活跃状态，直到它们检测到来自受损或感染细胞的信号。这些T细胞分裂并成熟，产生被称为效应细胞毒性淋巴样细胞（简称ctl）的活性T细胞群，这一过程被认为发生在白髓内。一种叫做细胞因子IL-12的小蛋白质参与了ctl的产生。细胞因子从其他免疫细胞中释放出来，导致被激活的T细胞分裂和成熟。长期以来，人们一直认为，在这个过程的早期，白髓中产生的IL-12足以驱动这个过程，但最近的研究表明，可能需要在血液可到达的脾脏其他区域持续产生IL-12。在这里，Shah等人研究了暴露于弓形虫病疫苗的小鼠中细胞毒性T细胞的产生。他们的实验表明，IL-12驱动CTL生产的早期和晚期。在早期阶段，T细胞对白细胞介素-12有反应，白细胞介素-12是由白髓中的一组淋巴树突状细胞分泌的。然而，在后期，T细胞从白髓转移到脾脏的其他部分，即边缘区和红髓，在那里，一组独特的“髓树突状”细胞也产生IL-12，并指导ctl的最终成熟。Shah等人的研究结果还表明，细胞毒性T细胞分裂和后来成熟产生ctl的过程涉及一系列严格控制的事件，这些事件主要发生在白髓外。这些观察结果为如何开发疫苗和其他治疗方法提供了新的视角，这些疫苗和治疗方法可以更有效地产生防止感染和癌症所需的ctl。DOI: http://dx.doi.org/10.7554/eLife.09017.002
The proinflammatory cytokine IL-12 drives the generation of terminally differentiated KLRG1+ effector CD8+ T cells. Using a Toxoplasma vaccination model, we delineate the sequence of events that naïve CD8+ T cells undergo to become terminal effectors and the differentiation steps controlled by IL-12. We demonstrate that direct IL-12 signaling on CD8+ T cells is essential for the induction of KLRG1 and IFN-γ, but the subsequent downregulation of CXCR3 is controlled by IL-12 indirectly through the actions of IFN-γ and IFN-γ-inducible chemokines. Differentiation of nascent effectors occurs in an extrafollicular splenic compartment and is driven by late IL-12 production by DCs distinct from the classical CD8α+ DC. Unexpectedly, we also found extensive proliferation of both KLRG1− and KLRG1+ CD8+ T cells in the marginal zone and red pulp, which ceases prior to the final KLRG1Hi CXCR3Lo stage. Our findings highlight the notion of an extrafollicular pathway for effector T cell generation. DOI: http://dx.doi.org/10.7554/eLife.09017.001 The immune system helps to protect us from cancer, infection by microbes and other diseases. There are several different types of immune cells that each have particular roles. For example, cytotoxic T cells can kill other cells in the body that are damaged or infected. These cells are found in various locations around the body—including a region of the spleen known as the white pulp—where they wait in an inactive state until they detect signals from a damaged or infected cell. These T cells divide and mature to produce populations of active T cells known as effector cytotoxic lymphoid cells (or CTLs for short), a process which is thought to occur within the white pulp. A small protein called cytokine IL-12 is involved in the production of CTLs. The cytokine is released from other immune cells and causes the activated T cells to divide and mature. It has long been believed that IL-12 produced in the white pulp early on in the process is sufficient to drive this process, but more recent work suggests that sustained production of IL-12 in other areas of the spleen that are accessible to the bloodstream may be needed. Here, Shah et al. studied the generation of cytotoxic T cells in mice that had been exposed to a vaccine against a disease called Toxoplasmosis. Their experiments show that IL-12 drives both the early and late stages of CTL production. In the early stages, the T cells respond to IL-12 that is secreted by a group of ‘lymphoid dendritic’ cells in the white pulp. However, in the later stages, the T cells move away from the white pulp to other parts of the spleen known as the marginal zone and red pulp, where a distinct group of ‘myeloid dendritic’ cells also produce IL-12 and direct the final maturation of the CTLs. Shah et al.'s findings also show that the process in which cytotoxic T cells divide and later mature to produce CTLs involves a series of tightly controlled events that mostly occur outside of the white pulp. These observations provide a new perspective on how to develop vaccines and other treatments that more efficiently generate the CTLs needed to protect against infections and cancer. DOI: http://dx.doi.org/10.7554/eLife.09017.002