Thymic expression of IL-4 and IL-15 after systemic inflammatory or infectious Th1 disease processes induce the acquisition of "innate" characteristics during CD8⁺ T cell development

Innate CD8+ T cells express a memory-like phenotype and demonstrate a strong cytotoxic capacity that is critical during the early phase of the host response to certain bacterial and viral infections. These cells arise in the thymus and depend on IL-4 and IL-15 for their development. Even though innate CD8+ T cells exist in the thymus of WT mice in low numbers, they are highly enriched in KO mice that lack certain kinases, leading to an increase in IL-4 production by thymic NKT cells. Our work describes that in C57BL/6 WT mice undergoing a Th1 biased infectious disease, the thymus experiences an enrichment of single positive CD8 (SP8) thymocytes that share all the established phenotypical and functional characteristics of innate CD8+ T cells. Moreover, through in vivo experiments, we demonstrate a significant increase in survival and a lower parasitemia in mice adoptively transferred with SP8 thymocytes from OT I—T. cruzi-infected mice, demonstrating that innate CD8+ thymocytes are able to protect against a lethal T. cruzi infection in an Ag-independent manner. Interestingly, we obtained similar results when using thymocytes from systemic IL-12 + IL-18-treated mice. This data indicates that cytokines triggered during the acute stage of a Th1 infectious process induce thymic production of IL-4 along with IL-15 expression resulting in an adequate niche for development of innate CD8+ T cells as early as the double positive (DP) stage. Our data demonstrate that the thymus can sense systemic inflammatory situations and alter its conventional CD8 developmental pathway when a rapid innate immune response is required to control different types of pathogens.固有CD8+ T细胞（innate CD8+ T cells）表达记忆样表型，并具备强效细胞毒活性，这在宿主针对某些细菌和病毒感染的早期应答阶段至关重要。此类细胞起源于胸腺，其发育依赖于白细胞介素4（IL-4）与白细胞介素15（IL-15）。尽管野生型（wild type, WT）小鼠的胸腺中固有CD8+ T细胞数量稀少，但在缺失特定激酶的基因敲除（knockout, KO）小鼠中，此类细胞显著富集，其机制在于后者胸腺内自然杀伤T细胞（thymic natural killer T, NKT）的IL-4产生量升高。本研究显示，在发生Th1偏向性感染的C57BL/6野生型小鼠中，其胸腺内会富集单阳性CD8（single positive CD8, SP8）胸腺细胞，此类细胞具备固有CD8+ T细胞所有已确立的表型与功能特征。此外，通过体内实验，我们证实：将感染克氏锥虫（Trypanosoma cruzi）的OT-I小鼠的SP8胸腺细胞过继转移至受体小鼠后，受体小鼠的存活率显著提升，虫血症水平显著降低，这表明固有CD8+胸腺细胞能够以抗原非依赖性方式抵御致死性克氏锥虫感染。值得注意的是，使用经全身性白细胞介素12（IL-12）与白细胞介素18（IL-18）处理的小鼠的胸腺细胞进行实验时，我们得到了相似的结果。该数据表明，在Th1型感染过程的急性期触发的细胞因子，可诱导胸腺产生IL-4并上调IL-15的表达，从而早在双阳性（double positive, DP）发育阶段就为固有CD8+ T细胞的发育构建了适宜的微环境。我们的研究数据证实，当机体需要快速启动固有免疫应答以抵御多种病原体时，胸腺能够感知全身性炎症状态，并改变其经典的CD8细胞发育通路。