Immunobiology Interdepartmental Graduate Program, Iowa State University, Ames, IA, USA.
Immunobiology Interdepartmental Graduate Program, Iowa State University, Ames, IA, USA; Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, USDA, Agricultural Research Service, Ames, IA, USA.
Vet Immunol Immunopathol. 2022 Jun;248:110418. doi: 10.1016/j.vetimm.2022.110418. Epub 2022 Apr 12.
As maternal passive immunity wanes at 6-8 weeks, young calves must rely on their own naïve and developing immune system for protection against pathogens. Typically, an infection in the young induces a T cell-mediated response, which skews towards a Th2 phenotype and results in a reduced effector response. Our study examines the implications this transitional period of immunocompetency has on cellular metabolism in young calves, focusing on effector function of CD4 T cells in comparison to those from adult cows. Results from sorted CD4 T cells from young calves and adult cows activated by α-CD3:α-CD28, show that young calves exhibit a significantly greater propensity to produce the Th2 cytokine, IL-4, in comparison to IFN-γ. Concomitantly, cells from young calves and adult cows exhibit no statistical difference in cell surface marker expression induced by α-CD3:α-CD28 stimulation. Metabolically, activated CD4 T cells from young calves show significantly greater utilization of mitochondrial respiration, measured by oxygen consumption rate (OCR), and greater glycolytic reserve, measured by extracellular acidification rate (ECAR). However, adult cows have a significantly higher change in glycolytic rate after α-CD3:α-CD28 stimulation compared to young calves. Further, CD4 T cells from young calves have an increased mRNA expression signature associated with glycolytic metabolism (GAPDH, HK2, FBP1, HIF1A) and Th2-associated metabolic signaling (RPTOR) in comparison to adult cows. The distinct metabolic phenotype and associated gene expression in activated CD4 T cells may be intrinsic drivers of the Th2-biased response by young calves. Additionally, CD4 recent thymic emigrant cells (RTEs) may further contribute to altered effector function, as they are preferential precursors to Tregs, and based on the microenvironment, have the propensity to polarize toward Th2. Evaluation of T cell master transcription regulators, as well as measuring signal joint T cell receptor excision circles between young calves and adult cows, we observed a significantly increased proportion of RTEs from sorted CD4 T cells. In this study, we show a unique metabolic profile exhibited by activated CD4 T cells from young calves in which mitochondrial respiration and glycolytic capacity is significantly increased compared to adult cows.
随着母体被动免疫在 6-8 周时减弱，小牛必须依靠自己幼稚和正在发育的免疫系统来抵御病原体。通常，幼畜感染会诱导 T 细胞介导的反应，这种反应偏向 Th2 表型，导致效应反应减少。我们的研究检查了这段免疫能力过渡时期对幼畜细胞代谢的影响，重点研究了幼稚 CD4 T 细胞与成年奶牛 CD4 T 细胞的效应功能。从幼畜和成年奶牛中分离的 CD4 T 细胞经 α-CD3:α-CD28 激活后的结果表明，与 IFN-γ 相比，幼畜产生 Th2 细胞因子 IL-4 的倾向性明显更大。同时，幼畜和成年奶牛的细胞经 α-CD3:α-CD28 刺激后，细胞表面标志物的表达无统计学差异。从代谢角度来看，幼稚 CD4 T 细胞经 α-CD3:α-CD28 刺激后，线粒体呼吸的利用明显增加，氧消耗率（OCR）增加，糖酵解储备增加，细胞外酸化率（ECAR）增加。然而，与幼畜相比，成年奶牛在经 α-CD3:α-CD28 刺激后糖酵解率的变化明显更高。此外，与成年奶牛相比，幼畜的幼稚 CD4 T 细胞中与糖酵解代谢（GAPDH、HK2、FBP1、HIF1A）和 Th2 相关代谢信号（RPTOR）相关的 mRNA 表达谱增加。幼稚 CD4 T 细胞中激活的独特代谢表型和相关基因表达可能是幼畜 Th2 偏向反应的内在驱动因素。此外，CD4 近期胸腺迁出细胞（RTE）可能通过更倾向于 Th2 而进一步改变效应功能，因为它们是 Treg 的优先前体，并且根据微环境，有向 Th2 极化的倾向。通过评估 T 细胞主转录调节因子，并测量幼畜和成年奶牛的 CD4 T 细胞信号接头 T 细胞受体切除环，我们观察到从幼稚 CD4 T 细胞中分离的 RTE 的比例显著增加。在这项研究中，我们展示了幼畜幼稚 CD4 T 细胞表现出的独特代谢谱，与成年奶牛相比，幼稚 CD4 T 细胞的线粒体呼吸和糖酵解能力明显增加。
