SFB 1054: Control and Plasticity of Cell-Fate Decisions in the Immune System

免疫细胞，特别是T细胞，表现出极大程度的发育可塑性，这表现在存在多个功能亚群，每个亚群都表现出特征性的效应子功能，细胞因子谱和组织特异性。一方面，αβ T细胞区室分离成不同的“谱系”（例如辅助细胞、杀伤细胞、调节性T细胞、iNKT细胞）是通过稳态发育程序印记的。另一方面，入侵病原体的遭遇，以及免疫稳态的许多其他扰动，如慢性感染，肿瘤或环境变化，可以引发“成熟”T细胞的适应性分化程序，导致获得独特的功能特征。自从发现经典的Th 1/Th 2范例，以及最近由用于在单细胞水平上对复杂细胞群体进行表型、转录和表观遗传分析的高度复杂的方法所引发，已经越来越清楚的是，这些明显不同的T细胞“亚群”中的许多代表具有不同程度的重叠特征的灵活状态的连续体。此外，有充分的证据表明，T细胞生命中的效应子阶段不一定是终末分化的表现;相反，武装的效应子通常保留相当程度的可塑性，使它们能够获得针对随后的免疫挑战和/或变化的条件而定制的“新”功能，这同样适用于先天免疫细胞，如NK细胞。在此背景下，CRC 1054已经着手探索免疫系统中细胞命运决定的这种显著可塑性的决定因素，既包括前体细胞在稳态条件下的发育决定，也包括“成熟”细胞对免疫挑战的灵活且通常可逆的适应。阐明控制免疫细胞命运决定的信号以及如何读取和解释这些信号提供了对免疫系统生物学的基本见解。同时，我们的方法与转化医学具有最高的相关性，因为它揭示了靶向免疫治疗的新前景。

Immune cells, and T cells in particular, display an enormous degree of developmental plasticity, which manifests itself in the existence of multiple functional subsets, each displaying characteristic effector functions, cytokine profiles and tissue specificities. On the one hand, the segregation of the αβ T cell compartment into distinct ‘lineages’ (e.g. helper cells, killer cells, regulatory T cells, iNKT cells) is imprinted through homeostatic developmental programs. On the other hand, the encounter of invading pathogens, but also many other perturbations of immune homeostasis such as chronic infection, neoplasia or environmental changes, can elicit adaptive differentiation programs in ‘mature’ T cells that result in the acquisition of distinct functional characteristics. Since the discovery of the classical Th1/Th2 paradigm, and more recently sparked by highly sophisticated methodology for phenotypic, transcriptional and epigenetic profiling of complex cell populations at the single cell level, it has become increasingly clear that many of these apparently distinct T cell ‘subsets’ represent a continuum of flexible states with a varying degree of overlapping characteristics. Moreover, there is ample evidence that the effector phase in a T cell’s life is not necessarily a manifestation of terminal differentiation; instead, armed effectors oftentimes retain a substantial degree of plasticity, allowing them to acquire ‘novel’ functions that are tailored to subsequent immune challenges and/or changing conditions, and this may likewise apply to innate immune cells such as NK cells. Against this background, the CRC 1054 has set out to explore the determinants of this remarkable plasticity of cell-fate decisions in the immune system, both in terms of the developmental decisions of precursor cells under homeostatic conditions and in terms of the flexible and often reversible adaptation of ‘mature’ cells to immune challenges. Elucidating the signals that control immune cell-fate decisions and how these signals are read and interpreted provides fundamental insights into the biology of the immune system. At the same time, our approach is of highest relevance for translational medicine, as it reveals novel perspectives for targeted immune therapies.