Novel methods for generating regulatory T-cells
Regulatory T-cells (Tregs) are key mediators of peripheral tolerance that can actively suppress effector T-cells, inhibit inflammation and mediate self-tolerance. Unlike naturally occurring Tregs (nTregs) which develop in the thymus, adaptive/induced (iTregs) develop in the periphery from naïve CD4+ Foxp3- T cells. In the presence of TGF-b, naïve T cells can be induced to express the transcription factor Foxp3 and become iTreg. These TGF-b induced Tregs potently suppress effector T cells.
The programmed death 1 receptor (PD-1) is upregulated on T cells upon their activation and highly expressed on Tregs. Its ligand, PD-L1, is expressed on antigen presenting cells (APCs) such as dendritic cells, macrophages and B cells, T cells, and a variety of nonhematopoietic cells including vascular endothelium, and at sites of immune privilege including the placenta and the eye. Interactions between PD-1 and PD-L help to regulate the balance between stimulatory and inhibitory signals needed for effective immunity and the maintenance of self-tolerance. In particular, this pathway is known to regulate peripheral CD4+ and CD8+ T cell tolerance, and is a key mediator of T cell dysfunction (“exhaustion”) during chronic viral infection.
Novel methods for inducing Tregs
Researchers in the Sharpe laboratory demonstrated that the PD-1:PD-L pathway is necessary for promoting iTreg development and sustaining Treg function. They further developed novel methods for inducing and maintaining Tregs by targeting PD-1 expressed on the surface of CD4+ T cells. Their findings are based on several lines of evidence:
- The capacity of APCs to convert naïve CD4+ T cells to iTregs is severely reduced when APCs are deficient in PD-L1
- Treating naïve CD4+ T cells with PD-L1-coated beads (along with anti-CD3 and anti-CD28) stimulates iTreg development in vitro
- Culturing iTregs with PD-L1-coated beads increases Foxp3 expression and enhances the suppressive function of iTreg
- PD-L1 and TGF- b have synergistic roles in regulating FoxP3+ iTreg development
- There is a marked reduction in iTreg conversion following transfer of naïve CD4+ T cells into mice deficient in PD-L1 and PD-L2 when compared to control mice
- Transfer of naïve CD4+ T cells into mice deficient in PD-L1 and PD-L2 rapidly produces a fatal inflammatory phenotype
This technology is available for worldwide, exclusive licensing and/or a collaborative research program with the Sharpe laboratory.
Intellectual Property Status: Patent(s) Pending
The goal of Treg cell-based therapies is to reduce inappropriate or undesired immune responses, such as the immune response to self (autoimmune disease) or the immune response to transplanted organs and tissues (transplant rejection). Agonists that target the cell surface receptor PD-1, such as its natural ligand PD-L1 or related agonists, are a promising new strategy to increase and or/maintain Treg cell activity in vivo, and may be useful for the treatment of autoimmune diseases and prevention of transplant rejection. PD-L1 agonists provide a novel means to sustain and enhance the suppressive function of Treg function in vivo while concomitantly suppressing the expansion and functions of activated T effector cells.