Department of Immunology and Microbiology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Cell Death Dis. 2023 Feb 11;14(2):111. doi: 10.1038/s41419-023-05619-0.
Cell death mechanisms in T lymphocytes vary according to their developmental stage, cell subset and activation status. The cell death control mechanisms of mucosal-associated invariant T (MAIT) cells, a specialized T cell population, are largely unknown. Here we report that MAIT cells express key necroptotic machinery; receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) protein, in abundance. Despite this, we discovered that the loss of RIPK3, but not necroptotic effector MLKL or apoptotic caspase-8, specifically increased MAIT cell abundance at steady-state in the thymus, spleen, liver and lungs, in a cell-intrinsic manner. In contrast, over the course of infection with Francisella tularensis, RIPK3 deficiency did not impact the magnitude of the expansion nor contraction of MAIT cell pools. These findings suggest that, distinct from conventional T cells, the accumulation of MAIT cells is restrained by RIPK3 signalling, likely prior to thymic egress, in a manner independent of canonical apoptotic and necroptotic cell death pathways.
T 淋巴细胞的细胞死亡机制因发育阶段、细胞亚群和激活状态而异。黏膜相关不变 T（MAIT）细胞是一种特殊的 T 细胞群体，其细胞死亡控制机制在很大程度上尚不清楚。在这里，我们报告 MAIT 细胞大量表达关键的坏死性细胞死亡机制；受体相互作用蛋白激酶 3（RIPK3）和混合谱系激酶结构域样（MLKL）蛋白。尽管如此，我们发现 RIPK3 的缺失，但不是坏死性效应物 MLKL 或凋亡半胱天冬酶-8 的缺失，以细胞内在的方式特异性地增加了胸腺、脾、肝和肺中 MAIT 细胞在稳态下的丰度。相比之下，在感染土拉弗朗西斯菌的过程中，RIPK3 缺陷并不影响 MAIT 细胞库的扩增或收缩的幅度。这些发现表明，与传统 T 细胞不同，MAIT 细胞的积累受到 RIPK3 信号的限制，可能在离开胸腺之前，以不依赖于经典凋亡和坏死性细胞死亡途径的方式。
