Engineered CD40-biosensor-expressing Treg cells as a cell therapy approach for inflammatory diseases

Area of Science:

• Immunology
• Cell Therapy
• Biotechnology

Background:

• Restoring immune tolerance via engineered regulatory T cell (Treg) therapy is a promising strategy for autoimmune and inflammatory diseases.
• A significant limitation is the frequent absence of known disease-driving antigens, hindering antigen-specific Treg cell therapy.
• Existing Treg therapies often lack specific targets, limiting their efficacy in diverse inflammatory conditions.

Purpose of the Study:

• To develop a novel artificial immune biosensor for Treg cells that bypasses the need for known disease antigens.
• To engineer Treg cells with a synthetic receptor targeting CD40-ligand (CD40L) expressed on activated T cells.
• To evaluate the therapeutic potential of CD40L-targeting Treg cells in a preclinical model.

Main Methods:

• Designed an artificial immune receptor (AIR) comprising a CD40-derived binding domain and intracellular signaling domains.
• Engineered Treg cells to express this CD40-AIR, enabling them to detect CD40L on activated T cells.
• Tested the efficacy of CD40-AIR Treg cells in a mouse model of graft-versus-host disease (GvHD).

Main Results:

• The CD40-AIR successfully triggered Treg activation programs, including effector molecule induction and proliferation, upon CD40L interaction.
• Transfer of CD40-AIR Treg cells significantly improved survival in a GvHD mouse model.
• Demonstrated immune control over the alloantigen-reactive T cell compartment in the GvHD model.

Conclusions:

• Engineering Treg cells with a CD40L-targeting sensor provides a novel therapeutic strategy for T cell-mediated inflammatory diseases.
• This approach circumvents the need for known disease antigens, broadening the applicability of Treg cell therapy.
• The developed CD40-AIR technology shows translational potential for treating a wide range of autoimmune and inflammatory conditions.