Tim-4 Promotes Tolerance at the Fetomaternal Interface.

Abstract

Objective: Acceptance of the fetus expressing allogeneic paternal antigens by the mother is a physiologic model of transplantation tolerance. The T-cell immunoglobulin domain and mucin domain (Tim) family members Tim-1, Tim-2, Tim-3, and Tim-4, are a group of newly described molecules with important immunological functions. Tim-4 has been shown to bind with phosphatidylserine (PtdSer) on apoptotic cells thereby facilitating their clearance, we explored if Tim-4 plays a role in maintaining tolerance at the fetomaternal interface (FMI). Study Design: An established fully allogeneic (CBAxB6) mating experimental setup was used. Pregnant mice were treated with a blocking anti-Tim-4 mAb or control Ig. Resorption of embryos at day 11.5 of pregnancy and litter size at term in treated versus control mice was determined. Placenta, uterus and draining LN were collected at different time points of pregnancy and macrophage, dendritic cells, myeloid derived suppressor cells (MDSCs) and T and B cell populations were characterized and compared between anti-Tim-4 and control groups. Results: Tim-4 is expressed on macrophages, myeloid derived suppressor cells (MDSCs) and on DCs at the uteroplacental interface. We examined whether treatment with anti-Tim-4 antibody would lead to an increase in apoptotic cells. Tim-4 blockade did not result in an increase in apoptosis of any of the immune cells. Further, Tim-4 expressing uterine macrophages and DCs isolated from pregnant anti-Tim-4 treated mice were not defective in phagocytosis of apoptotic cells. Alloreactive CD4, CD8 T cells and B cells were increased following anti-Tim-4 treatment with a decrease in B but not T regulatory cells. Collectively, this data suggest that Tim-4-PtdSer interaction is not a dominant contributor to tolerance at FMI and that Tim-4, via its interaction with a different receptor possibly Tim-1 leads to costimulation. Conclusion: Our data demonstrate that Tim-4 expressing immune cells play a critical in fetomaternal tolerance in vivo by affecting the pool of alloreactive T and B cells.