Yuzefpolskiy Yevgeniy, Baumann Florian M, Penny Laura A, Studzinski George P, Kalia Vandana, Sarkar Surojit
Center for Molecular Immunology and Infectious Diseases, Department of Veterinary and Biomedical Sciences, and The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA; and.
Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ.
J Nutr. 2014 Dec;144(12):2073-82. doi: 10.3945/jn.114.202895. Epub 2014 Oct 15.
Vitamin D insufficiency is associated with broad-ranging human disease sequelae such as bone disease, cancer, cardiovascular disease, allergy, autoimmune disorders, diabetes, and infectious diseases. Disease risk and severity of a large proportion of the nonskeletal disorders heavily involve the cytotoxic cluster of differentiation (CD) 8 T lymphocyte (CTL) arm of cellular adaptive immunity. Considering the importance of vitamin D in CTL-dependent diseases, there is a critical need for systematic in-depth explorations into the role of vitamin D deficiency in generation and maintenance of CTL immunity during infections and vaccinations.
With the use of wild-type (WT) vitamin D-sufficient mice and the vitamin D receptor knockout (Vdr(-/-)) mouse model of in vivo deficiency of vitamin D signaling, we systematically analyzed the impact of vitamin D deficiency on antigen-specific effector and memory CD8 T cell responses to acute viral and bacterial infections.
WT and Vdr(-/-) mice were infected with lymphocytic choriomeningitis virus, a natural mouse pathogen, and antigen-specific CTL responses were analyzed during priming, expansion, contraction, and memory phases. Magnitude, breadth, cytokine production, and localization of antiviral effector and memory CTLs to lymphoid and nonlymphoid tissues were specifically assessed.
The absence of vitamin D signals led to 1) aberrant CD8 T cell effector differentiation (∼2-fold lower granzyme B and reduced B cell lymphoma 2; P ≤ 0.05) and enhanced contraction (∼15% increase; P ≤ 0.05) in antigen-specific CTLs; 2) a significantly restricted (P ≤ 0.05) breadth of the antigen-specific CD8 T cell effector and memory repertoire; and 3) preferential localization of effector (∼2.5-fold increase; P ≤ 0.01) and memory (∼5-fold increase; P ≤ 0.001) CD8 T cells to the lymph nodes compared to nonlymphoid tissues.
Our data show a previously unrecognized impact of vitamin D deficiency on the quantity, quality, breadth, and location of CD8 T cell immunity to acute viral and bacterial infections.
维生素D缺乏与多种人类疾病后遗症相关，如骨病、癌症、心血管疾病、过敏、自身免疫性疾病、糖尿病和传染病。很大一部分非骨骼疾病的疾病风险和严重程度在很大程度上涉及细胞适应性免疫的细胞毒性分化簇（CD）8 T淋巴细胞（CTL）分支。考虑到维生素D在依赖CTL的疾病中的重要性，迫切需要系统深入地探讨维生素D缺乏在感染和疫苗接种期间CTL免疫的产生和维持中的作用。
通过使用野生型（WT）维生素D充足的小鼠和体内维生素D信号缺乏的维生素D受体敲除（Vdr(-/-)）小鼠模型，我们系统地分析了维生素D缺乏对抗原特异性效应和记忆CD8 T细胞对急性病毒和细菌感染反应的影响。
WT和Vdr(-/-)小鼠感染天然小鼠病原体淋巴细胞脉络丛脑膜炎病毒，并在启动、扩增、收缩和记忆阶段分析抗原特异性CTL反应。特别评估了抗病毒效应和记忆CTL在淋巴细胞和非淋巴细胞组织中的数量、广度、细胞因子产生和定位。
维生素D信号的缺失导致：1）抗原特异性CTL中CD8 T细胞效应分化异常（颗粒酶B降低约2倍，B细胞淋巴瘤2减少；P≤0.05）和收缩增强（增加约15%；P≤0.05）；2）抗原特异性CD8 T细胞效应和记忆库的广度显著受限（P≤0.05）；3）与非淋巴细胞组织相比，效应CD8 T细胞（增加约2.5倍；P≤0.01）和记忆CD8 T细胞（增加约5倍；P≤0.001）优先定位于淋巴结。
我们的数据显示了维生素D缺乏对CD8 T细胞对急性病毒和细菌感染免疫的数量、质量、广度和位置的前所未有的影响。
