人巨细胞病毒编码蛋白UL23调控 HCMV-specific T 细胞增殖、活性及分化的机理

人巨细胞病毒HCMV感染的一个标志性特征是与T细胞免疫系统特殊的相互作用。抗原特异性T细胞受体（TCR）和细胞因子介导的两个信号斧协调T细胞活化。我们前期研究发现HCMV编码蛋白UL23能抑制细胞因子INF-γ信号通路的活性、调控T细胞中INF-γ合成；RNA-seq检测发现UL23控制多个与TCR、细胞因子信号相关的病毒免疫逃逸基因的表达。据此提出假设“UL23自身及通过控制多个免疫逃逸病毒基因的表达，调控T细胞响应HCMV感染的过程”。本项目拟采用大数据（如scRNA-seq）与传统生物学研究方法相结合的方式，比较全病毒与缺失UL23突变病毒感染过程中，抗原提呈细胞活性和T细胞响应的差异，以抗原加工、提呈，及T细胞激活为主线，阐明UL23调控T细胞增殖、活性和分化的机理。研究成果将为研发有效免疫学方法防控HCMV感染奠定基础，并能拓展人们对HCMV感染过程中T细胞响应的认识。

Human Cytomegaloviruse (HCMV) are ubiquitous viruse that have co‑evolved with host over millennia. T cell development, differentiation, and maintenance are orchestrated by 2 key signaling axes: the antigen specific TCR and cytokine-mediated signals. The majority of the world’s population is infected with HCMV. One hallmark of CMV infection is the complicated interactions between CMV and T cells response, which is a major barrier in the progress of vaccine development and anti-virus immunotherapy. We have shown previously that HCMV-coding protein UL23 interferes with interferon-γ-dependent JAK/STAT1 signal transduction, and inhibits the synthesis of some cytokines such as interferon-γ in T cells. And by means of RNA-seq, UL23 was found to control the expression of HCMV-coding genes, especially those related with viral immunomodulation，which target many aspects of the immune response, including the evasion of T cell responses, the interferon response, and perturbation of immunomodulatory Pathways. Based on our finding, we further hypothesize that UL23 might modify T cell responses for HCMV infection through controlling the expression of HCMV-coding immunomodulating genes. In this study, by interrogating the differences of immune response of antigen presenting cell and T cells to the entire HCMV-Towne and HCMV-del UL23-Towne (mutation without UL23 gene ) infection will help us to understand the molecular mechanism how UL23 regulates the activity of T cells through the modulation of antigen processing and presenting. This study will enable the development of effective immunotherapeutic treatments for HCMV infection and widen our knowledge of the functional capacity of T cells in response to virus infection.