Programmed Death Ligand‐1‐Overexpressing Donor Exosomes Mediate Donor‐Specific Immunosuppression by Delivering Co‐Inhibitory Signals to Donor‐Specific T Cells

Abstract

AbstractProgrammed death ligand‐1 (PD‐L1) and donor antigens are critical for donor immature dendritic cells (DCs) targeting donor‐specific T cells to induce transplant tolerance. This study aims to clarify whether DC‐derived exosomes (DEX) with donor antigens (H2b) and high levels of PD‐L1 expression (DEXPDL1+) can help to suppress graft rejection. In this study, it is demonstrated that DEXPDL1+ presents donor antigens, as well as PD‐L1 co‐inhibitory signals, directly or semi‐directly via DCs to H2b‐reactive T cells. This dual signal presentation can prolong the survival of heart grafts from B6 (H2b) mice but not from C3H (H2k) mice by inhibiting T cell activation, inducing activated T cell apoptosis, and modulating the balance of T cell differentiation from inflammatory to regulatory. Additionally, even though DEXPDL1+ treatment cannot induce tolerance after short‐term treatment, this study provides a new vehicle for presenting co‐inhibitory signals to donor‐specific T cells. This novel strategy may facilitate the realization of donor‐specific tolerance via the further optimization of drug‐loading combinations and therapeutic regimens to elevate their killing ability.