Epigenetic regulation of iNKT2 cell adoptive therapy on the imbalance of iNKT cell subsets in thymus of RA mice.

Epigenetic regulation affects the development and differentiation of iNKT cells. Our previous study found that the number of iNKT cells in thymus of RA mice was reduced and the ratio of subsets was unbalanced, but the related mechanism remains unclear. We adopted an adoptive infusion of iNKT2 cells with specific phenotypes and functions to RA mice and used the α-Galcer treatment group as control. The findings revealed that: 1. Adoptive treatment of iNKT cells decreased the proportion of iNKT1 and iNKT17 subsets in the thymus of RA mice, and increased the proportion of iNKT2 subsets. 2. Following treatment with iNKT cells, the expression of PLZF in thymus DP T cells was increased whereas the expression of T-bet in thymus iNKT cells was decreased in RA mice. 3. Adoptive therapy reduced the modification levels of H3Kb7me3 and H3K4me3 in the promoter regions of Zbtb16 (encoding PLZF) and Tbx21 (encoding T-bet) gene in thymus DP T cells and iNKT cells, and the reduction of H3K4me3 was particularly significant in the cell treatment group. Furthermore, adoptive therapy also upregulated the expression of UTX (histone demethylase) in thymus lymphocytes of RA mice. As a result, it is hypothesized that adoptive therapy of iNKT2 cells may affect the level of histone methylation in the promoter region of important transcription factor genes for iNKT development and differentiation, thereby directly or indirectly correcting the imbalance of iNKT subsets in the thymus of RA mice. These findings offer a fresh rationale and concept for the management of RA that targets.