San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy.
Transplant and Metabolic/Bariatric Surgery Unit, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy.
BMJ Open Diabetes Res Care. 2020 Apr;8(1). doi: 10.1136/bmjdrc-2019-000772.
Insulin resistance, defined as tissue inflammation leading to type 2 diabetes, is a feature of obesity. The immune system has been implicated in its pathogenesis, but the role of adaptive immunity in humans remains uncertain. Here, we aim to determine whether specific phenotypic and functional properties of visceral adipose tissue (VAT)-derived CD4 conventional T cells (Tconv) and CD8 T cells are associated with dysglycemia in human obesity.
Peripheral blood and the stromal vascular fraction of obese patients without dysglycemia (n=23), with impaired fasting glucose or type 2 diabetes (n=17), and non-diabetic lean controls (n=11) were studied. Characterization of memory, activation profile, cytokine production, proliferative capacity, cytotoxic potential and transforming growth factor-β-mediated suppression of CD4 Tconv and CD8 T cells was performed. Correlation between anthropometric/metabolic parameters and VAT-derived T cell subsets was determined.
In the VAT of the overall obese population, reduced frequency of interferon-γ-producing or tumor necrosis factor-α-producing CD4 (ie, T helper 1, Th1) and CD8 (ie, cytotoxic type 1, Tc1) T cells, as well as interleukin-17-producing CD8 T cells (ie, Tc17), was evident when compared with lean controls. However, enrichment of Tc1 cells, together with the impaired ability of CD4 and CD8 T cells to be suppressed, distinguished the visceral fat of obese patients with dysglycemia from the one of non-diabetic obese patients. Moreover, accumulation of Th1 and Tc1 cells in the VAT correlated with anthropometric and metabolic parameters.
Here, we define the VAT-specific characteristics of T cells in human obesity, showing that accumulation of Tc1 cells and T cell resistance to suppression can be harmful to the development of obesity-induced diabetes. These findings open new directions to investigate immunological targets in the obesity setting.
胰岛素抵抗是 2 型糖尿病的特征之一，其定义为组织炎症导致的糖尿病，是肥胖的一个特征。免疫系统已被牵涉到其发病机制中，但适应性免疫在人类中的作用仍不确定。在这里，我们旨在确定内脏脂肪组织（VAT）衍生的 CD4 常规 T 细胞（Tconv）和 CD8 T 细胞的特定表型和功能特性是否与人类肥胖中的糖血症有关。
研究了无糖血症的肥胖患者（n=23）、空腹血糖受损或 2 型糖尿病患者（n=17）和非糖尿病瘦对照者（n=11）的外周血和基质血管部分。对记忆、激活谱、细胞因子产生、增殖能力、细胞毒性潜力以及转化生长因子-β对 CD4 Tconv 和 CD8 T 细胞的抑制作用进行了表征。确定了人体测量/代谢参数与 VAT 衍生 T 细胞亚群之间的相关性。
在整个肥胖人群的 VAT 中，与瘦对照者相比，产生干扰素-γ或肿瘤坏死因子-α的 CD4（即 Th1）和 CD8（即细胞毒性 1，Tc1）T 细胞以及产生白细胞介素-17 的 CD8 T 细胞（即 Tc17）的频率降低。然而，Tc1 细胞的富集以及 CD4 和 CD8 T 细胞抑制能力受损，将糖血症肥胖患者的内脏脂肪与非糖尿病肥胖患者的内脏脂肪区分开来。此外，Th1 和 Tc1 细胞在 VAT 中的积累与人体测量和代谢参数相关。
在这里，我们定义了人类肥胖中 T 细胞的 VAT 特异性特征，表明 Tc1 细胞的积累和 T 细胞对抑制的抵抗力可能对肥胖诱导的糖尿病的发展有害。这些发现为研究肥胖环境中的免疫靶标开辟了新的方向。
