Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity.

Area of Science:

• Immunology
• Cellular and Molecular Immunology
• Autoimmunity

Background:

• Reprogramming autoreactive CD4+ effector T (Teff) cells into immunosuppressive regulatory T (Treg) cells is a potential treatment for autoimmune diseases.
• The stability and function of these reprogrammed Tregs in inflammatory environments are not well understood.

Purpose of the Study:

• To investigate the stability and efficacy of reprogrammed Tregs generated through epigenetic modification of Teff cells.
• To compare the therapeutic potential of these novel reprogrammed Tregs against existing Treg-based strategies.

Main Methods:

• Demethylation of core Treg identity genes in Teff cells to create lineage-stable Effector T cell Reprogrammed Tregs (ER-Tregs).
• Adoptive transfer of ER-Tregs in mouse models of autoimmune neuroinflammation before and after disease onset.
• Comparative analysis of ER-Treg efficacy against Foxp3-overexpressing Teff cells, induced Tregs, and endogenous Tregs.

Main Results:

• ER-Tregs demonstrated lineage stability under inflammatory conditions.
• A single transfer of ER-Tregs prevented and arrested autoimmune neuroinflammation in mice.
• ER-Tregs provided superior protection compared to other Treg types, due to inherited autoantigen specificity and preserved effector functions.

Conclusions:

• Epigenetic reprogramming of autoreactive Teff cells generates potent and stable Tregs.
• ER-Tregs represent a promising therapeutic strategy for treating refractory autoimmune conditions like neuroinflammation.