Human Inhibitory Receptor Immunoglobulin-Like Transcript 2 Amplifies CD11b+Gr1+ Myeloid-Derived Suppressor Cells That Promote Long-Term Survival of Allografts

BACKGROUND: The expression of human leukocyte antigen (HLA)-G during allogeneic recognition is associated with better graft acceptance. The inhibitory receptor immunoglobulin-like transcript (ILT)-2 is expressed on activated T cells and serves to shut down T-cell activation, culminating in T-cell death, or induction of anergy. One of the potential mechanisms in the immunosuppressive accomplishment of HLA-G-ILT2 interactions involves the expansion of myeloid-derived suppressor cells (MDSCs). The potential of MDSCs in transplantation has not yet been exploited. METHODS: (1) Detailed phenotypic characteristics, immunosuppressive potential of MDSCs expanded by means of inhibitory receptor ILT2 and its ligands, and allogeneic transplant-activated MDSCs were obtained in mice. (2) Oligo- and real-time pathway-specific polymerase chain reaction arrays were performed to characterize ILT2-specific MDSCs. (3) Skin allograft survival after adoptive transfer of MDSCs was studied. RESULTS: Engagement of ILT2 receptors, especially by HLA-G, expanded the population of MDSCs with enhanced suppressive activity. Adoptive transfer of MDSCs generated by ILT2 receptor and its ligands prolonged graft survival in recipients of allogeneic skin transplant. We have proposed pathways for enhancement of immunosuppressive activities and expansion of MDSCs by ILT2 and HLA-G. CONCLUSIONS: Our results suggest that induction of MDSCs using ILT2 inhibitory receptor/HLA-G ligand may be an attractive strategy for preventing rejection of immunogenic organs or tissues in clinical transplantation.