Physiology and pathology of T-cell aging
Physiology and pathology of T-cell aging
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DOI：
10.1093/intimm/dxaa006
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发表时间：
2020-04-01
影响因子：
4.4
通讯作者：
Hamazaki, Yoko
中科院分区：
文献类型：
--
作者：
Minato, Nagahiro;Hattori, Masakazu;Hamazaki, Yoko
获得性免疫功能随着时间的推移显示出可识别的变化与有机体老化。这些变化包括T细胞功能障碍，这可能是老年人对感染和可能的各种慢性年龄相关疾病的抵抗力下降的基础。T细胞功能障碍可能发生在不同的阶段，从幼稚细胞到免疫应答期间的分化终末阶段。产生幼稚T细胞的胸腺显示出异常的早期退化，导致青春期后T细胞输出的进行性减少，但外周T细胞数量通过幼稚T细胞的抗原非依赖性稳态增殖来维持，该增殖由与自身肽和稳态细胞因子相关的主要组织相容性复合体驱动，保留了多样的库。然而，广泛的稳态增殖可能导致功能失调的CD 4（+）T细胞的出现，其特征类似于衰老细胞，称为衰老相关T（SA-T）细胞，其随着年龄的增长而增加和积累。在慢性病毒感染等情况下，T细胞功能障碍也可能通过持续的抗原刺激（称为耗竭）发展，从而防止由于过度免疫应答而导致的可能的免疫病理学。耗尽的T细胞是通过检查点受体如PD-1的作用产生的，并且可以通过受体阻断来逆转。值得注意的是，尽管在其常规T细胞抗原受体介导的增殖中有缺陷，但SA-T细胞分泌丰富的促炎因子，如骨桥蛋白，使人联想到SA分泌表型。在小鼠模型中的一系列实验表明，SA-T细胞参与全身性自身免疫以及组织应激后的慢性组织炎症。在这篇综述中，我们讨论了与衰老相关的T细胞功能障碍的生理方面及其在年龄相关疾病和可能的癌症中的潜在病理参与。
Acquired immune function shows recognizable changes over time with organismal aging. These changes include T-cell dysfunction, which may underlie diminished resistance to infection and possibly various chronic age-associated diseases in the elderly. T-cell dysfunction may occur at distinct stages, from naive cells to the end stages of differentiation during immune responses. The thymus, which generates naive T cells, shows unusually early involution resulting in progressive reduction of T-cell output after adolescence, but peripheral T-cell numbers are maintained through antigen-independent homeostatic proliferation of naive T cells driven by the major histocompatibility complex associated with self-peptides and homeostatic cytokines, retaining the diverse repertoire. However, extensive homeostatic proliferation may lead to the emergence of dysfunctional CD4(+) T cells with features resembling senescent cells, termed senescence-associated T (SA-T) cells, which increase and accumulate with age. In situations such as chronic viral infection, T-cell dysfunction may also develop via persistent antigen stimulation, termed exhaustion, preventing possible immunopathology due to excessive immune responses. Exhausted T cells are developed through the effects of checkpoint receptors such as PD-1 and may be reversed with the receptor blockade. Of note, although defective in their regular T-cell antigen-receptor-mediated proliferation, SA-T cells secrete abundant pro-inflammatory factors such as osteopontin, reminiscent of an SA-secretory phenotype. A series of experiments in mouse models indicated that SA-T cells are involved in systemic autoimmunity as well as chronic tissue inflammation following tissue stresses. In this review, we discuss the physiological aspects of T-cell dysfunction associated with aging and its potential pathological involvement in age-associated diseases and possibly cancer.