LAG-3 Mediates Acute Rejection & Memory in Mouse Transplantation

摘要

Lymphocyte Activation Gene-3 (LAG-3) is a soluble protein and transmembrane protein receptor expressed on lymphocytes such as immunosuppressive regulatory T cells. Our goal was to evaluate the effect of LAG-3 on transplantation outcomes, specifically rejection and cellular memory response to donor antigen, by comparing graft survival and IFN-l secretion to donor antigen in C57BL/6 LAG-3-/- versus wild-type mouse recipients of DBA/2 grafts. We found that LAG-3 deletion accelerates rejection time and enhances IFN-l secretion among heart or skin graft recipients. FACS analysis of memory T cells demonstrated disproportionate increases in effector T cell subsets, consistent with a heightened rejection response. Although the absence of LAG-3 enhanced rejection of heart and skin grafts, it did not abrogate tolerance of spontaneously accepted kidney allografts. To further understand the mechanism of LAG-3 signaling and the potential importance of dendritic cells, we cultured donor dendritic cells in a tolerogenic milieu with recipient T cells and found increased PD-1 and IL-10 expression among T cells. Lastly, we performed soluble LAG-3 injections and adoptive transfers of LAG-3+/+ cells into knock-out graft recipients. This demonstrated that the presence of LAG-3 on T cells is critical for mediation of rejection, while LAG-3 on dendritic cells downregulates donor-specific IFN-l secretion. Our data suggest that in addition to LAG-3's effects on proliferation and activation, LAG-3 may also affect differentiation of precursor CD4+ T cells. Additionally, these data indicate the importance of dendritic cell-mediated control of the memory response in a LAG- 3-dependent manner.