Antigen specificity acquisition of adoptive CD4⁺ regulatory T cells via acquired peptide-MHC class I complexes

The Ag-specific CD4⁺ regulatory T (Tr) cells play an important role in immune suppression in autoimmune diseases and antitumor immunity. However, the molecular mechanism for Ag-specificity acquisition of adoptive CD4⁺ Tr cells is unclear. In this study, we generated IL-10- and IFN-γ-expressing type 1 CD4⁺ Tr (Tr1) cells by stimulation of transgenic OT II mouse-derived naive CD4⁺ T cells with IL-10-expressing adenovirus (AdVIL-10)-transfected and OVA-pulsed dendritic cells (DC_OVA/IL-10). We demonstrated that both in vitro and in vivo DC_OVA/IL-10-stimulated CD4⁺ Tr1 cells acquired OVA peptide MHC class (pMHC) I which targets CD4⁺ Tr1 cells suppressive effect via an IL-10-mediated mechanism onto CD8⁺ T cells, leading to an enhanced suppression of DC_OVA-induced CD8⁺ T cell responses and antitumor immunity against OVA-expressing murine B16 melanoma cells by ≈700% relative to analogous CD4⁺ Tr1 cells without acquired pMHC I. Interestingly, the nonspecific CD4⁺25⁺ Tr cells can also become OVA Ag specific and more immunosuppressive in inhibition of OVA-specific CD8⁺ T cell responses and antitumor immunity after uptake of DCOVA-released exosomal pMHC I complexes. Taken together, the Ag-specificity acquisition of CD4⁺ Tr cells via acquiring DC's pMHC I may be an important mean in augmenting CD4⁺ Tr cell suppression.