Cobbold Stephen P, Adams Elizabeth, Howie Duncan, Waldmann Herman
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
Front Immunol. 2018 Jun 18;9:1381. doi: 10.3389/fimmu.2018.01381. eCollection 2018.
During an immune response, naïve CD4 T cells proliferate and generate a range of effector, memory, and regulatory T cell subsets, but how these processes are co-ordinated remains unclear. A traditional model suggests that memory cells use mitochondrial respiration and are survivors from a pool of previously proliferating and glycolytic, but short-lived effector cells. A more recent model proposes a binary commitment to either a memory or effector cell lineage during a first, asymmetric cell division, with each lineage able to undergo subsequent proliferation and differentiation. We used improved fixation and staining methods with imaging flow cytometry in an optimized system that indicates a third model. We found that cell fates result from stochastic decisions that depend on GITR co-stimulation and which take place before any cell division. Effector cell commitment is associated with mTORC2 signaling leading to uropodium development, while developing memory cells lose mitochondria, have a nuclear localization of NFκB and depend on TGFβ for their survival. Induced, T helper subsets and foxp3 regulatory T cells were found in both the effector and memory cell lineages. This model of T cell differentiation is well suited to testing how manipulation of cytokine, nutrient, and other components of the microenvironment might be exploited for therapeutic purposes.
在免疫反应过程中，初始CD4 T细胞增殖并产生一系列效应T细胞、记忆T细胞和调节性T细胞亚群，但这些过程是如何协调的仍不清楚。传统模型认为，记忆细胞利用线粒体呼吸作用，是先前增殖且进行糖酵解但寿命短暂的效应细胞群体中的幸存者。最近的一个模型提出，在第一次不对称细胞分裂期间，细胞会对记忆细胞或效应细胞谱系做出二元决定，每个谱系都能够进行后续的增殖和分化。我们在一个优化的系统中使用了改进的固定和染色方法以及成像流式细胞术，这表明了第三种模型。我们发现，细胞命运是由随机决定产生的，这些决定依赖于GITR共刺激，且发生在任何细胞分裂之前。效应细胞的决定与导致尾足发育的mTORC2信号传导相关，而正在发育的记忆细胞会丢失线粒体，NFκB定位于细胞核，并且其存活依赖于TGFβ。在效应细胞和记忆细胞谱系中均发现了诱导性T辅助亚群和foxp3调节性T细胞。这种T细胞分化模型非常适合测试如何利用细胞因子、营养物质和微环境的其他成分的调控来达到治疗目的。
