Characterization of an Expanded IL-10-Producing-Suppressive T Cell Population Associated with Immune Tolerance

An increase in the number of glucocorticoid-induced tumor necrosis factor receptor-family related gene/protein (GITR)⁺CD25^- (or fork-head box protein 3: Foxp3^-) CD4⁺ T cells, after treating a mouse model of arthritis with fingolimod (FTY720), and a pathogenic antigen may play a key role in the establishment of immune tolerance. In this study, we characterized a specific expanded T cell subset in this population. Mice with glucose-6-phosphate isomerase peptide (GPI_325-339)-induced arthritis were treated with FTY720 (1 mg/kg, per os) and GPI_325-339 (10 µg/mouse, intravenously) for five days, starting from the onset of symptoms. The expanded GITR⁺CD25^- (or Foxp3^-) CD4⁺ T cell population and its cytokine production were examined using flow cytometry. Furthermore, time-dependent changes in T-bet and/or early growth response gene 2 (Egr-2) expression in this T cell subset were examined. The density of T cell immunoreceptors with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)⁺CD39⁺ cell subset in the GITR⁺Foxp3^-CD4⁺ T cell population was significantly increased only in the combined treatment group, compared to that in the untreated and single-treatment groups. In the TIGIT⁺CD39⁺GITR⁺Foxp3^-CD4⁺ T cell population, T-bet⁺Egr-2⁺/T-bet⁺Egr-2^- cell ratio increased in the latter stage of the treatment. Furthermore, this T cell subset, which corresponded to a T helper 1 (Th1) response, produced high levels of both interleukin (IL)-10 and interferon (IFN)-γ. In conclusion, expanded TIGIT⁺CD39⁺GITR⁺Foxp3^-CD4⁺ T cells shifted from an effector Th1 to IL-10-producing-suppressor T cell phenotype, which may promote an immune-tolerant state.