Tfh and B cells in HIV/SIV pathogenesis and vaccination

Tfh 和 B 细胞在 HIV/SIV 发病机制和疫苗接种中的作用

• 批准号: 8745610
• 负责人: Richard A Koup
• 金额: $ 127.39万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745610
• 关键词: Animals; Antibodies; Antibody Formation; B-Lymphocytes; CD4 Positive T Lymphocytes; Cells; Chronic; Exhibits; Frequencies; Genes; Goals; HIV; HIV Infections; Helper-Inducer T-Lymphocyte; Human; Immunoglobulins; Infection; Interleukin-4; Interleukin-6; Location; Macaca mulatta; Molecular Profiling; Monkeys; Pathogenesis; Phenotype; Population Heterogeneity; Process; Production; Protocols documentation; SIV; Structure of germinal center of lymph node; Vaccination; cytokine; immune activation; lymph nodes; neutralizing antibody; trafficking

We have investigated the phenotype, function, location and molecular signature of follicular CD4 T helper cells (TFH) in rhesus macaques. Similar to human TFH, they are characterized by a CCR7lowPD-1highCTLA-4highICOShighCXCR4high phenotype and represent a heterogeneous population with respect to cytokine function. Production of Th1 cytokines was compromised while IL-4 production was augmented in a highly differentiated (CD150low) subpopulation of TFH cells that was also characterized by decreased survival, cycling, and trafficking capacity. Compared to non-TFH cells, TFH cells exhibited a distinct gene profile that was significantly altered by SIV infection. TFH cells were found to be infected by SIV yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. These processes contribute to B cell and immunoglobulin abnormalities in SIV, and by extension HIV, infection.

我们研究了恒河猴滤泡性CD 4辅助性T细胞（TFH）的表型、功能、位置和分子特征。与人TFH相似，其特征为CCR 7低PD-1高CTLA-4高ICOS高CXCR 4高表型，代表了细胞因子功能的异质性群体。Th 1细胞因子的产生受到损害，而IL-4的产生在高度分化（CD 150低）的TFH细胞亚群中增加，其特征还在于存活、循环和运输能力降低。与非TFH细胞相比，TFH细胞表现出不同的基因谱，SIV感染显著改变。TFH细胞被发现被SIV感染，然而，在一些动物中，这些细胞实际上在慢性SIV感染期间积累。在SIV感染期间，全身免疫激活和IL-6产生增加有助于驱动TFH分化。TFH的积累与激活的生发中心B细胞和SIV特异性抗体的频率增加有关。这些过程导致SIV感染时B细胞和免疫球蛋白异常，进而导致HIV感染。