The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

中文翻译：

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老年人结肠记忆 CD4 T 细胞免疫调节分子表达降低

与衰老相关的低水平慢性炎症状态的病因可能是多因素的，但许多动物和人类研究表明，胃肠道免疫系统的功能衰退是潜在的驱动因素。肠道组织驻留记忆 T 细胞在介导保护性免疫和维持肠道稳态方面发挥着关键作用，但很少有研究调查衰老对人体肠道 T 细胞免疫的影响。为了确定衰老是否影响人类大肠中的 CD4 T 细胞免疫，我们利用多色流式细胞仪测量结肠固有层 (LP) CD4 T 细胞频率和免疫调节标志物在年轻人中的表达（平均值 ± SEM：38 ± 1.5岁）和年龄更大（77 ± 1.6 岁）的成年人。为了确定细胞特异性，我们评估了相同供体中的结肠 LP CD8 T 细胞频率和表型。为了探究组织特异性，我们在一个单独的年龄相仿的人群中评估了外周血 (PB) CD4 T 细胞中的同一组标志物。作为总 LP 单核细胞一部分的结肠 CD4 T 细胞的频率在老年人中较高，而每克组织中结肠 LP CD4 T 细胞的绝对数量在两个年龄组中相似。来自老年人和年轻人的 LP CD4 T 细胞表现出 CTLA-4、PD-1 和 Ki67 表达降低。两个年龄组的 Bcl-2、CD57、CD25 水平和活化 CD38+HLA-DR+CD4 T 细胞的百分比相似。在记忆 PB CD4 T 细胞中，年龄较大仅与 CD57 表达增加有关。仅在 CTLA-4 表达中观察到 LP CD8 T 细胞的显着年龄影响，在来自老年人的细胞上观察到较低水平的表达。年龄越大与 LP CD4 T 细胞上共抑制受体 CTLA-4 和 PD-1 的表达减少有关。来自老年人的结肠 LP CD8 T 细胞也表现出 CTLA-4 表达降低。在较老的 PB 记忆 CD4 T 细胞中未观察到这些与年龄相关的特征。结肠 LP T 细胞上共抑制受体表达的下降可能通过降低限制正在进行的 T 细胞对肠道微生物挑战的反应的能力而导致局部和全身炎症。