Cloning, expression, and functional characterization of TL1A-Ig

Area of Science:

• Immunology
• T cell biology
• Inflammation research

Background:

• Tumor Necrosis Factor superfamily member 15 (TL1A) is a ligand for TNFR superfamily member 25 (TNFRSF25).
• Previous studies showed TNFRSF25 agonist antibody (4C12) expands regulatory T cells (Tregs) in vivo.
• The distinct functions of the physiological ligand TL1A compared to agonist antibodies remain to be fully elucidated.

Purpose of the Study:

• To investigate the effects of a soluble TL1A-Ig fusion protein on T cell populations, particularly Tregs.
• To assess the in vivo efficacy of TL1A-Ig in expanding Tregs and its therapeutic potential in allergic inflammation models.

Main Methods:

• Generation of a soluble mouse TL1A-Ig fusion protein.
• In vitro assessment of TL1A-Ig effects on Treg and conventional T cell proliferation and function.
• In vivo administration of TL1A-Ig to mice to evaluate Treg expansion, maintenance, and therapeutic effects in a mouse model of allergic lung inflammation.

Main Results:

• TL1A-Ig induced rapid proliferation of both Foxp3(+) Tregs and CD4(+)Foxp3(-) conventional T cells in vitro.
• In vivo, TL1A-Ig treatment led to a significant expansion of Tregs (30-35% of CD4(+) T cells) within 5 days, which could be maintained for at least 20 days.
• TL1A-Ig-expanded Tregs exhibited activation/memory markers (KLRG1, CD103) and were highly suppressive ex vivo. Treatment was protective against allergic lung inflammation.

Conclusions:

• Soluble TL1A-Ig fusion proteins are potent agents for stimulating Treg proliferation in vivo.
• TL1A-Ig effectively expands and maintains Treg populations, offering a controllable method for Treg-based therapies.
• TL1A-Ig demonstrates therapeutic efficacy in a mouse model of asthma by modulating immune responses in the lung.