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

免疫细胞，尤其是T细胞，表现出巨大的发育可塑性，表现为存在多个功能亚群，每个亚群都具有独特的效应功能、细胞因子谱和组织特异性。一方面，αβT细胞亚群分离成不同的“谱系”(如辅助细胞、杀伤细胞、调节性T细胞、iNKT细胞)是通过体内平衡发育程序印记的。另一方面，遇到入侵的病原体，以及许多其他免疫稳态的扰动，如慢性感染、肿瘤或环境变化，都可以诱导成熟T细胞的适应性分化程序，导致获得不同的功能特征。自从经典的Th1/Th2模式被发现以来，以及最近在单细胞水平上用于复杂细胞群体的表型、转录和表观遗传学分析的高度复杂的方法学所引发的，越来越明显的是，许多明显不同的T细胞‘亚群’代表了具有不同程度重叠特征的灵活状态的连续体。此外，有充分的证据表明，T细胞生命中的效应器阶段并不一定是终末分化的表现；相反，武装效应器往往保持相当程度的可塑性，使它们能够获得针对随后的免疫挑战和/或不断变化的条件而量身定做的“新”功能，这可能同样适用于天然免疫细胞，如NK细胞。在此背景下，CRC1054已着手探索免疫系统中细胞命运决定的这种非凡可塑性的决定因素，既包括体内平衡条件下前体细胞的发育决定，也包括“成熟”细胞对免疫挑战的灵活且往往是可逆的适应。阐明控制免疫细胞命运决定的信号以及这些信号是如何被解读和解释的，有助于对免疫系统生物学的基本洞察。同时，我们的方法对转化医学具有最高的相关性，因为它揭示了靶向免疫疗法的新视角。

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.