Partial loss of Sorting Nexin 27 resembles age- and Down syndrome-associated T cell dysfunctions

IF 5.2 2区 医学 Q1 GERIATRICS & GERONTOLOGY
Cristina Rodriguez-Rodriguez, Natalia González-Mancha, Ane Ochoa-Echeverría, Rosa Liébana, Isabel Merida
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Abstract

Sorting Nexin 27 (SNX27)-retromer complex facilitates cargo recycling from endosomes to the plasma membrane. SNX27 downregulation in neurons, as the result of Trisomy 21 (T21), has been linked with cognitive deficits due to impairment of AMPA and NMDA receptor recycling. Studies in human T cell lines likewise demonstrated that SNX27 regulates the correct delivery of cargoes to the immune synapse limiting the activation of pro-inflammatory pathways. Nevertheless, the physiological consequences of partial SNX27 loss in T cell homeostasis are still unclear. In this study, we have explored the consequences of T cell specific partial SNX27 downregulation in mice. T cells with partial SNX27 deficiency show a marked deficit in the CD4+ T cell pool, a hallmark of aging in mice and humans, and a well-characterized comorbidity of individuals with Down syndrome (DS). When analyzed ex vivo, CD4+ T cells with partial SNX27 deletion demonstrate enhanced proliferation but diminished IL-2 production. In contrast, the CD8+ population show enhanced expression of pro-inflammatory cytokines and lytic enzymes. This mouse model supports the relevance of SNX27 in the organization of the immune synapse, previously described in cell lines, as well as in the control of T cell homeostasis. Individuals with DS experiment an acceleration of the aging process, which particularly affects the immune and central nervous systems. Thus, we hypothesize that reduced SNX27 expression in DS could contribute to the dysregulation of these systems and further research in SNX27 will shed light on the molecular factors underlying the phenotypes observed in people with DS and its contribution to aging.
分拣内毒素 27 的部分缺失与年龄和唐氏综合征相关的 T 细胞功能障碍相似
分选内含蛋白 27(SNX27)-转录因子复合物促进了货物从内体到质膜的再循环。由于 21 三体综合征(T21),神经元中的 SNX27 下调与 AMPA 和 NMDA 受体循环受损导致的认知障碍有关。在人类 T 细胞系中进行的研究同样表明,SNX27 可调节货物向免疫突触的正确传递,从而限制促炎途径的激活。然而,部分 SNX27 缺失对 T 细胞稳态的生理影响仍不清楚。在这项研究中,我们探讨了小鼠T细胞特异性SNX27部分下调的后果。部分 SNX27 缺失的 T 细胞在 CD4+ T 细胞池中显示出明显的缺陷,这是小鼠和人类衰老的标志,也是唐氏综合征(DS)患者的一种特征明显的合并症。在进行体外分析时,部分 SNX27 缺失的 CD4+ T 细胞显示出增殖增强,但 IL-2 生成减少。与此相反,CD8+细胞群的促炎细胞因子和裂解酶表达增强。这一小鼠模型证实了 SNX27 与免疫突触的组织以及 T 细胞稳态控制的相关性。DS 患者的衰老过程会加速,这尤其会影响免疫系统和中枢神经系统。因此,我们推测SNX27在DS患者中的表达减少可能会导致这些系统的失调,对SNX27的进一步研究将揭示在DS患者中观察到的表型的分子因素及其对衰老的贡献。
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来源期刊
Immunity & Ageing
Immunity & Ageing GERIATRICS & GERONTOLOGY-IMMUNOLOGY
CiteScore
10.20
自引率
3.80%
发文量
55
期刊介绍: Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.
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