LDLR+ Monocytic Myeloid-derived Suppressor Cells Attenuate Allograft Rejection in Liver Transplantation.

Abstract

Background and aims: Liver transplant rejection significantly affects patient prognosis. Myeloid-derived suppressor cells (MDSCs), known for their potent immunoregulatory functions, represent a promising target for managing liver transplant rejection. This study aimed to systematically characterize the diversity of MDSC subsets and their context-dependent functions, particularly within the context of transplant tolerance.

Methods: We analyzed clinical and murine liver transplants using single-cell RNA sequencing, bulk RNA sequencing, flow cytometry, multiplex immunohistochemistry, and co-culture assays to phenotype MDSC subsets.

Results: Single-cell RNA sequencing analysis of human and murine samples revealed MDSC involvement in transplant rejection. In mice, MDSC scores followed a normal distribution during the first week post-transplant and correlated with clinical flow cytometry data at one month. A distinct LDLR⁺ monocytic MDSC (M-MDSC) subset was identified and confirmed through spatial mapping by multiplex immunohistochemistry. Flow cytometry demonstrated dynamic changes in LDLR⁺ M-MDSCs across tissues (liver, spleen, peripheral blood, bone marrow, and lymph nodes), with a peak during acute rejection. Co-culture experiments showed that LDLR-/- M-MDSCs exhibited reduced Arg-1/iNOS expression and an impaired capacity to induce inhibitory receptors (TIGIT, PD1, CTLA-4) or suppress effector molecules (GZMB, IFN-γ, IL-2) in CD8⁺ T cells.

Conclusions: These findings highlight the critical role of MDSCs in liver transplant rejection. LDLR⁺ M-MDSCs exhibited enhanced immunosuppressive properties, underscoring their potential clinical relevance in mitigating rejection and promoting immune tolerance.