Our previous studies showed that an induced Th17 autoreactive T-cell response in EAU was preceded by increased activation of γδ T cells,
29,31 and increased generation of the CD25
+ DC subset.
30 Moreover, autoreactive Th17 responses are compromised in mice with dysfunctional γδ T cells
26–29 and in mice incapable of generating CD25
+ DCs during the immunization process.
30 Based on these studies, we hypothesize that prevention of γδ T-cell activation or inhibition of CD25
+ DC might allow us to restrain the intensity of the Th17 autoreactive T-cell response in EAU.
28,29,31 γδ T cells can be activated via multiple pathways in the absence of TCR engagement, including ligation of NKG2D receptor,
39 exposure to cytokines
40 or TLR ligands,
41 or binding to surface molecules expressed by myeloid cells.
42 An effective way that can prevent γδ T-cell activation has not be investigated adequately to our knowledge. Using a well-established autoimmune disease model of EAU and an assay system established in our laboratory, we examined the mechanism by which RA treatment inhibits the autoimmune development. Our results supported the previous findings that RA-treated mice showed a significantly depressed autoreactive T-cell response, particularly with regard to the subset of autoreactive T cells that express IL-17. We also showed that ATRA treatment can, in vitro and in vivo, effectively inhibit the expansion of CD25
+ DCs and γδ T-cell activation, thereby restraining the Th17 autoreactive T-cell response. The results of this study further support our previous report that CD25
+ DCs possess strongest γδ T-cell stimulatory activity,
30 and that control of γδ T-cell activation deserves to be a valuable way of controlling the Th17 autoreactive T cells in autoimmune disease. We also showed that decreased pathogenic T-cell response, rather than enhanced regulatory T-cell activity, can be attributed directly to the inhibitory effect of RA. Our results that the ATRA treatment, especially in vivo administration, has little effect on Foxp3
+ cells, appears to differ from those of Keino et al.
19 However, these two studies differed in a number of approaches, even though it is premature to predict the exact cause for the possible differences. For example, in the study of Keino et al., the examined Foxp3
+ cells were from naïve mice, the stimulant was anti-CD3+CD28, and the response was in the presence of TGF-β. Our study targeted T cells of immunized mice after in vitro activation with the immunizing antigen and in the absence of TGF-β. All of these listed differences may have caused the difference in outcome.