T cell activation and IFNγ modulate organ dysfunction in LPS-mediated inflammation

Area of Science:

• Immunology
• Cellular Biology
• Pathophysiology

Background:

• Lipopolysaccharide (LPS) challenge models inflammation-induced organ dysfunction.
• The impact of T cell activation on LPS-mediated organ dysfunction and immune responses remains unclear.

Purpose of the Study:

• To investigate the combined effects of T cell activation (using anti-CD3ε antibody) and LPS on organ dysfunction and immune responses in vivo.
• To elucidate the mechanisms underlying T cell and dendritic cell interactions in this model.

Main Methods:

• In vivo administration of anti-CD3ε (CD3) antibody and varying doses of LPS.
• Monitoring mortality, organ dysfunction, cytokine production (IFNγ, IL12p70), and cell surface marker expression (CD40, MHCII, PD1) on T cells and dendritic cells (cDCs).
• Investigating the effects of cytokine blockade (IFNγ, IL12p40) in different experimental groups.

Main Results:

• High-dose LPS (LPSHi) caused 60% mortality.
• Combining CD3 with a 10-fold lower LPS dose (CD3LPSLo) resulted in similar mortality and severe organ dysfunction.
• CD3LPSLo increased IFNγ and IL12p70 production, upregulated CD40 and MHCII on cDCs, prevented PD1 expression, and generated cytolytic CD4 and CD8 T cells.
• CD3LPSLo responses were sensitive to IFNγ or IL12p40 blockade, unlike LPSHi.

Conclusions:

• The combination of T cell receptor (TCR) activation and LPS dysregulates T cell activation.
• This interaction exacerbates LPS-associated organ dysfunction and mortality through T cell and cDC crosstalk.
• Targeting these specific T cell and dendritic cell interactions may offer therapeutic strategies for inflammatory conditions.