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.

中文翻译：

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T 细胞衰老的生理学和病理学。


随着机体衰老，获得性免疫功能随着时间的推移显示出可识别的变化。这些变化包括 T 细胞功能障碍，这可能是老年人对感染的抵抗力下降以及可能导致各种与年龄相关的慢性疾病的原因。 T 细胞功能障碍可能发生在免疫反应期间的不同阶段，从幼稚细胞到分化末期。产生幼稚 T 细胞的胸腺表现出异常早期的退化，导致青春期后 T 细胞输出逐渐减少，但外周 T 细胞数量通过与抗原无关的幼稚 T 细胞稳态增殖来维持，该增殖由相关的主要组织相容性复合物驱动。具有自身肽和稳态细胞因子，保留了多样化的功能。然而，广泛的稳态增殖可能导致功能失调的 CD4+ 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而发生，称为衰竭，从而防止由于过度免疫反应而可能发生的免疫病理学。耗尽的 T 细胞是通过检查点受体（例如 PD-1）的作用而产生的，并且可以通过受体阻断来逆转。值得注意的是，尽管 SA-T 细胞的常规 T 细胞抗原受体介导的增殖存在缺陷，但它会分泌丰富的促炎因子，例如骨桥蛋白，这让人想起 SA 分泌表型。小鼠模型中的一系列实验表明，SA-T 细胞参与系统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与年龄相关疾病和可能的癌症的潜在病理参与。