DOCK2 Protects against Bacterial Sepsis by Constraining T helper 1 Response

Shusen Ye^1,2Linzi Huang¹Yuhao Zheng¹Shanshan Liu¹Xiangyang Wang³Haoyuan Yu^4,5Lisi Zhu¹Texi Liang¹Yifei Wang²Chunmin Zhang⁶FAN WU^7*Lilin Ye^1*Yingjiao Cao^1,8*

• ¹Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
• ²Institute of Immunological Innovation and Translation, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
• ³Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China
• ⁴Department of Hepatic Surgery and Liver Transplantation Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
• ⁵Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
• ⁶Pediatric Intensive Care Unit, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
• ⁷Department of Neonatology, Guangzhou Key Laboratory of Neonatal Intestinal Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
• ⁸Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

Sepsis is a systemic host response to infection with life-threatening consequence which ranks among the top ten causes of death worldwide. Nevertheless, our understanding of the molecular and cellular impact of sepsis remains rudimentary. Here, we identified dedicator of cytokinesis 2 (DOCK2) is a critical downregulating factor for LPS signal pathways. DOCK2-deficient mice were highly sensitive to LPS-induced sepsis and Escherichia coli sepsis with increased levels of inflammatory cytokines, especially IFN-γ which were mainly due to hyperresponsive T helper 1 cells. Ulteriorly, we verified the vital role of DOCK2-mediated Th1 cells in sepsis by neutralizing both IFN-γ and CD4 and found both of which blockade reduced the severity of sepsis in Dock2 -/- mice. Mechanically, DOCK2-mediated cell cycle progression and cytokine signaling act in concert to govern peripheral Th1 cell fate. Taken together, our data indicates that DOCK2 acts as a protective role in regulating systemic inflammation and multi-organ injury in bacterial sepsis by constraining Th1 response.