CNRS, Immunopathology and therapeutic chemistry/Laboratory of excellence MEDALIS, Institute of molecular and cellular biology (IBMC), Strasbourg, France.
University of Strasbourg, Strasbourg, France.
Sci Rep. 2018 Apr 13;8(1):5951. doi: 10.1038/s41598-018-23993-0.
Studies of mice deficient for autophagy in T cells since thymic development, concluded that autophagy is integral to mature T cell homeostasis. Basal survival and functional impairments in vivo, limited the use of these models to delineate the role of autophagy during the immune response. We generated Atg5 distal Lck (dLck)-cre mice, with deletion of autophagy only at a mature stage. In this model, autophagy deficiency impacts CD8 T cell survival but has no influence on CD4 T cell number and short-term activation. Moreover, autophagy in T cells is dispensable during early humoral response but critical for long-term antibody production. Autophagy in CD4 T cells is required to transfer humoral memory as shown by injection of antigen-experienced cells in naive mice. We also observed a selection of autophagy-competent cells in the CD4 T cell memory compartment. We performed in vitro differentiation of memory CD4 T cells, to better characterize autophagy-deficient memory cells. We identified mitochondrial and lipid load defects in differentiated memory CD4 T cells, together with a compromised survival, without any collapse of energy production. We then propose that memory CD4 T cells rely on autophagy for their survival to regulate toxic effects of mitochondrial activity and lipid overload.
研究人员在胸腺发育后对缺乏自噬的 T 细胞进行了研究，得出的结论是自噬对于成熟 T 细胞的稳态至关重要。由于体内基础存活和功能受损，这些模型的使用受到限制，无法阐明自噬在免疫反应中的作用。我们生成了 Atg5 远端 Lck(dLck)-cre 小鼠，仅在成熟阶段删除自噬。在该模型中，自噬缺陷会影响 CD8 T 细胞的存活，但对 CD4 T 细胞数量和短期激活没有影响。此外，自噬在 T 细胞中在早期体液反应中并不必需，但对长期抗体产生至关重要。如在幼稚小鼠中注射有经验的抗原细胞所示，CD4 T 细胞中的自噬对于转移体液记忆是必需的。我们还观察到 CD4 T 细胞记忆区室中存在自噬功能细胞的选择。我们进行了记忆 CD4 T 细胞的体外分化，以更好地表征自噬缺陷记忆细胞。我们发现分化的记忆 CD4 T 细胞中存在线粒体和脂质负荷缺陷，以及存活能力受损，而没有能量产生崩溃。然后我们提出记忆 CD4 T 细胞依赖自噬来维持其存活，以调节线粒体活性和脂质过载的毒性作用。
