# DOCK2 protects against bacterial sepsis by constraining T helper 1 response

## TL;DR

This study shows that DOCK2 helps protect against bacterial sepsis by controlling Th1 immune responses, which could lead to new treatments for sepsis.

## Contribution

The study identifies DOCK2 as a novel protective factor in sepsis by modulating Th1 cell activity and systemic inflammation.

## Key findings

- DOCK2-deficient mice are more susceptible to sepsis with elevated inflammatory cytokines like IFN-γ.
- Blocking IFN-γ or CD4+ T cells reduces sepsis severity in DOCK2-deficient mice.
- DOCK2 regulates Th1 cell fate through cell cycle and cytokine signaling.

## Abstract

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.

A mouse sepsis model was established through LPS induction and Escherichia coli (E. coli) infection. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to detect T helper 1 (Th1) cell subsets and serum pro-inflammatory cytokines in septic mice. Additionally, in vivo neutralization experiments were conducted to block IFN-γ and CD4+ T cells, respectively, to explore the regulatory effect of DOCK2 on septic mice. Finally, the regulatory mechanism of DOCK2 was analyzed using an in vivo RNA-seq system.

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 E. coli sepsis with increased levels of inflammatory cytokines, especially IFN-γ which were mainly due to hyperresponsive Th1 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.

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. These findings provide new targets for immunomodulatory therapy of sepsis, suggesting that targeting the DOCK2-Th1 axis may become a new strategy to improve systemic inflammatory responses associated with bacterial infections.