T淋巴细胞稳态增殖,由T细胞抗原受体与自身肽/主要组织相容性复合物的结合驱动,和通过常见的含γ链的细胞因子受体的信号,对于维持T细胞区室至关重要,并且受Fas死亡受体(Fas,CD95)。在没有Fas的情况下,Fas缺陷型淋巴细胞增殖自发突变(lpr)小鼠积累稳态扩增的T细胞。稳态扩展的连续轮次的功能后果没有很好的定义。因此,我们检查了鼠野生型和Fas缺陷的lprCD8T细胞亚群的基因表达谱,这些亚群经历了不同量的稳态增殖,如它们的CD44表达水平所定义的。和CD4-CD8-TCRαβ+T细胞亚群,其由CD8+T细胞的广泛稳态扩增产生。我们的研究表明,反复的T细胞稳态增殖导致整体基因表达变化,包括细胞溶解蛋白如Fas-配体和颗粒酶B以及抑制蛋白如程序性细胞死亡蛋白1(PD-1)和淋巴细胞活化蛋白3(Lag3)的逐渐上调。这些发现为增强的T细胞稳态扩增如何导致经常观察到的同时自身炎症和免疫缺陷综合征的临床悖论提供了解释,并为控制慢性刺激的T细胞的调控程序提供了进一步的见解。
T lymphocyte homeostatic proliferation, driven by the engagement of T cell antigen receptor with self-peptide/major histocompatibility complexes, and signaling through the common γ-chain-containing cytokine receptors, is critical for the maintenance of the T cell compartment and is regulated by the Fas death receptor (Fas, CD95). In the absence of Fas, Fas-deficient lymphoproliferation spontaneous mutation (lpr) mice accumulate homeostatically expanded T cells. The functional consequences of sequential rounds of homeostatic expansion are not well defined. We thus examined the gene expression profiles of murine wild-type and Fas-deficient lpr CD8+ T cell subsets that have undergone different amounts of homeostatic proliferation as defined by their level of CD44 expression, and the CD4-CD8-TCRαβ+ T cell subset that results from extensive homeostatic expansion of CD8+ T cells. Our studies show that recurrent T cell homeostatic proliferation results in global gene expression changes, including the progressive upregulation of both cytolytic proteins such as Fas-Ligand and granzyme B as well as inhibitory proteins such as programmed cell death protein 1 (PD-1) and lymphocyte activating 3 (Lag3). These findings provide an explanation for how augmented T cell homeostatic expansion could lead to the frequently observed clinical paradox of simultaneous autoinflammatory and immunodeficiency syndromes and provide further insight into the regulatory programs that control chronically stimulated T cells.