ICOS ligand costimulation is required for T-cell encephalitogenicity.

Area of Science:

• Immunology
• Neuroimmunology
• T-cell Biology

Background:

• Inducible T-cell Costimulator (ICOS) and its ligand (ICOSL) are critical for T-cell responses.
• ICOS-dependent costimulation plays a role in T-cell activation and effector function.

Purpose of the Study:

• To investigate the role of the ICOS:ICOSL interaction in the activation and encephalitogenic potential of CD4(+) T-cells.
• To determine the impact of blocking ICOS signaling on T-cell survival, cytokine production, and experimental autoimmune encephalomyelitis (EAE) development.

Main Methods:

• MBP-reactive transgenic CD4(+) T-cells were activated in vitro in the presence of ICOS-Ig.
• T-cell transfer experiments were performed to assess EAE induction.
• Apoptosis markers (BAX/BCL-2 ratio) and cytokine production (IL-2, IFN-gamma, IL-10) were analyzed.
• ICOS-Ig was administered to mice with established EAE to evaluate therapeutic potential.

Main Results:

• ICOS-Ig blockade inhibited the ability of T-cells to transfer EAE, despite their entry into the brain.
• ICOS-Ig treatment increased apoptosis in CD4(+) T-cells, particularly memory cells, indicated by an elevated BAX/BCL-2 mRNA ratio.
• IL-2 production remained unaffected, suggesting ICOS-ligand independence for IL-2.
• IFN-gamma and IL-10 production were suppressed by ICOS-Ig.
• Administration of ICOS-Ig post-EAE onset ameliorated clinical symptoms.

Conclusions:

• The ICOS:ICOSL pathway provides essential costimulatory signals for encephalitogenic T-cell activation, survival, and effector function, distinct from CD28.
• Blocking ICOS signaling presents a potential therapeutic strategy for autoimmune diseases like EAE.
• ICOSL signaling is critical for maintaining the viability and pathogenic potential of autoreactive T-cells.