The targeted delivery of a DNA methyltransferase inhibitor to either CD4+ or CD8+ T cells can ameliorate lupus-like disease in mice, according to new findings published in JCI Insight. These findings highlight the importance of DNA hypermethylation in systemic lupus erythematosus (SLE) and the therapeutic potential of cell-specific inhibition of DNA methylation.

T cells are major contributors to SLE pathogenesis, and T cell abnormalties (such as a defective regulatory T cell and/or expanded double-negative T cell compartment) are common in patients.

Credit: Springer Nature Limited

“Previous work suggests that global demethylation defects in patients with SLE contribute to the development of autoimmunity and pathology”, explains George Tsokos, corresponding author of the study. “We hypothesized that demethylation affects the function of various immune cell subsets differently.”

The researchers delivered a demethylating agent (5-azacytidine; 5-Aza) to specific T cell subsets using nanolipogels coated with either anti-CD4 or anti-CD8 antibodies. CD4-specific DNA demethylation resulted in the expansion of regulatory T cells, whereas CD8-specific DNA demethylation resulted in a decrease in the generation of double-negative T cells in mice. Both approaches ameliorated established disease in lupus-prone mice, unlike treatment with unloaded nanolipogels or with free 5-Aza.

“Previous data from our group suggest that CD8+ T cells convert to double-negative T cells through transcriptional silencing of CD8α and CD8β,” says Hao Li, first author on the study. “Loss of CD8 expression on CD8+ T cells could lead to a reduction in cytotoxic capacity, which is important for controlling the development of autoimmunity and lupus-like disease.”

In a mouse model of T cell-mediated autoimmunity using adoptively transferred T cells, they detected a simultaneous loss of both CD8 and perforin expression in the CD8+ T cells, which was inhibited with 5-Aza (targeted to the transferred T cells).

CD8-specific DNA demethylation resulted in a decrease in the generation of double-negative T cells

“Our findings suggest that the role of DNA methylation in SLE development is rather complex,” remarks Li. “We would like to apply this approach to other immune cell subsets known to contribute to SLE pathogenesis including macrophages, B cells, and tissue resident cells,” concludes Tsokos.