Innate modulation of autoimmune, regulatory, and effector B cells in adipose tissue

肥胖是一种关键的全球流行病，是可预防的死亡的主要原因，也是健康飙升的来源 护理费用。目前，超过三分之二的美国成年人超重，至少三分之一被认为超重 太胖了。越来越多的人认识到肥胖与内脏脂肪的慢性低度炎症有关。 组织和一系列相关代谢异常，包括胰岛素抵抗，脂肪肝， 以及2型糖尿病(T2D)，以及心脏病、哮喘、癌症和中风等相关疾病。 为了帮助控制这种流行病，了解关键免疫细胞的具体作用将是至关重要的。 或加重肥胖患者的炎症和代谢性疾病。 虽然许多驻留在瘦脂肪组织中的B细胞是产生IL-10的B调节细胞(BREG)，但B细胞 肥胖小鼠脂肪组织中细胞数量增加可能在慢性炎症中起作用 肥胖内脏脂肪组织(VAT)的特征。B细胞抗原呈递的联合变化， 小鼠肥胖和人类T2D期间的细胞因子谱和抗体谱可能有助于代谢 支持T细胞介导的炎症和胰岛素抵抗的疾病；然而，VAT B细胞的原因 肥胖或T2D期间的调节失调仍不清楚。INKT细胞也占健康人T细胞的10%-20% 脂肪组织，但这一比例在肥胖的老鼠和人类中减少。剩余的iNKT细胞的激活 通过糖脂激动剂α半乳糖神经酰胺(αGalCer)，减轻许多炎症症状 肥胖，这表明它们的丢失是免疫环境失调的另一个重要因素 在肥胖或相关的自身免疫性或炎症性疾病期间。 我们已经证明，αGalCer激活的小鼠iNKT细胞直接与脾B细胞相互作用，产生 抗原特异性免疫球蛋白，扩增IL-10+Breg细胞。有趣的是，我们还发现被激活的iNKT细胞可以 VAT中IL-10+Breg细胞也有类似的增加，这表明它们在维持脂肪动态平衡方面发挥了关键作用。 在一个相关的慢性炎症小鼠模型中，我们发现iNKT细胞也可以被中性粒细胞许可为 调节脾内自身反应性B细胞，但中性粒细胞对iNKT细胞及其下游的影响 对脂肪组织中B细胞的影响尚不清楚。我们假设早期的中性粒细胞 在肥胖小鼠的脂肪组织中，INFUX培养出iNKT细胞，以驱动从Breg到B效应细胞的致病转变。 INKT细胞激活也可能减少肥胖期间的代谢性疾病，部分原因是通过重建健康的 调节性B细胞群。这些研究将加深我们对关键的免疫调节细胞的理解 健康和慢性炎症性肥胖脂肪组织中的人群及其与许多其他疾病的关系 炎症性疾病和相关疾病，如T2D、癌症和中风。

Obesity is a critical global epidemic, a leading cause of preventable death, and a source of skyrocketing health care costs. Currently more than two thirds of US adults are overweight and at least one third are considered obese. It is increasingly appreciated that obesity is linked to chronic, low-grade inflammation in visceral adipose tissue and an associated spectrum of metabolic abnormalities including insulin resistance, fatty liver disease, and type-2 diabetes (T2D) in addition to related conditions such as heart disease, asthma, cancer, and stroke. To help control this epidemic, it will be critical to understand the specific roles of key immune cells which regulate or exacerbate inflammation and metabolic disease in obese patients. While many of the B cells resident in lean adipose tissue are IL-10-producing B regulatory cells (Breg), B cell numbers increase in adipose tissue of obese mice and may play a role in the chronic inflammation characteristic of obese visceral adipose tissue (VAT). Combined alterations in B cell antigen presentation, cytokine profile, and antibody repertoire during obesity in mice and T2D in humans likely contributes to metabolic disease by supporting T cell mediated-inflammation and insulin resistance; however, the cause of VAT B cell dysregulation during obesity or T2D remains unknown. iNKT cells also make up 10-20% of T cells in healthy adipose tissue but this proportion is reduced in obese mice and humans. Activation of the remaining iNKT cells by the glycolipid agonist, αGalactosylceramide (αGalCer), reduces many of the inflammatory symptoms of obesity, suggesting their loss is another important contributor to the dysregulated immune environment evident during obesity or related autoimmune or inflammatory diseases. We have shown that αGalCer-activated murine iNKT cells directly interact with splenic B cells to produce antigen-specific IgG and expand IL-10+ Breg cells. Interestingly, we also see that activated iNKT cells can mediate a similar increase in IL-10+ Breg cells in VAT, suggesting they play a key role in maintaining adipose homeostasis. In a related murine model of chronic inflammation, we find that iNKT cells can also be licensed by neutrophils to regulate autoreactive B cells in spleen, but the influence of neutrophils on iNKT cells and their downstream effects on B cells in adipose tissue remains as yet uncharacterized. We hypothesize that an early neutrophil influx educates iNKT cells in adipose tissue of obese mice to drive a pathogenic shift from Breg to B effector cells. iNKT cell activation may also reduce metabolic disease during obesity in part by re-establishing a healthy regulatory B cell population. These studies will enhance our understanding of key regulatory immune cell populations in healthy and chronically inflamed obese adipose tissue with implications for many other inflammatory diseases and related conditions such as T2D, cancer, and stroke.