Brd4 Regulates the Homeostasis of CD8 + T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation

• Published in: Frontiers in immunology 2021-08, Vol.12, p.728082
• Main Authors: Peng, Zhilin, Zhang, Yiwen, Ma, Xiancai, Zhou, Mo, Wu, Shiyu, Song, Zheng, Yuan, Yaochang, Chen, Yingshi, Li, Yuzhuang, Wang, Guanwen, Huang, Feng, Qiao, Yidan, Xia, Baijing, Liu, Weiwei, Liu, Jun, Zhang, Xu, He, Xin, Pan, Ting, Xu, Hanshi, Zhang, Hui
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antigens, Viral - immunology; antiviral immunity; Azepines - pharmacology; Brd4; CD8+ T cell homeostasis; CD8+ T cell proliferation; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - transplantation; CD8-Positive T-Lymphocytes - virology; Cell Proliferation - drug effects; Chlorocebus aethiops; Disease Models, Animal; glucose metabolism; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Glycolysis; Host-Pathogen Interactions; Immunology; Lymphocyte Activation - drug effects; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - metabolism; Lymphocytic Choriomeningitis - virology; Lymphocytic choriomeningitis virus - immunology; Lymphocytic choriomeningitis virus - pathogenicity; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - genetics; Mitochondria - immunology; Mitochondria - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Triazoles - pharmacology; Vero Cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.728082

CD8 T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8 T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8 T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8 T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8 T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8 T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8 T cell response to antigen stimulation, as deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8 T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8 T cell-mediated immune surveillance and also provides a potential immunomodulation target.