Despite remarkable improvements in short term transplant survival, the long-term outcome of allografts remains poor in the clinic, and most transplants are eventually lost due to chronic rejection. m-TOR pathway plays an important role in acquired immune cell activation and acute rejection, but its role in innate immune cell activation and chronic rejection remains poorly defined. This experiment is intended to explore the exact mechanism of m-TOR pathway in regulating the activation of innate immune cells and chronic allograft loss. We used a mouse heart transplant model to examine cell types that infiltrate chronically rejected allografts and their roles in chronic allograft loss. We found that treatment of B6 recipients with a single dose of CTLA-4Ig prolonged the survival of Balb/c heart allografts (MST=31d) as compared to untreated controls (MST=8 days). Histologically, the CTLA-4Ig treated grafts showed signs of extensive chronic rejection characterized by heavy leukocyte infiltration and prominent neointima formation. Phenotypically, macrophages were a key infiltrating cell type in the vascular lesions in the grafts. Then we established a conditional knockout mice in which the m-TOR gene was missing only in myeloid system (using Lyz - Cre and mTOR – Flox mice). Compared to the wild-type recipients, the graft survival time of conditional knockout recipients was significantly prolonged (60 day vs.30 day), which was associated with markedly reduced infiltrating immune cells and neointima generation in the grafts. Flow cytometry analysis revealed that the number of infiltrating macrophages and CD3+ lymphocytes decreased significantly. Interestingly, the ratio of mature macrophages who express CD86 exhibited the most remarkable reduction. More importantly, among the infiltrating lymphoid cells, both the number and ratio of CD4 +cells were significantly decreased (17.7% vs 0.96%), but this change was not obvious in spleen. In vitro, we found that during the process of bone marrow-derived macrophage differentiation, the expression of co-stimulating molecules CD80 and CD86 was lower in m-TOR myeloid knockout mice as compared to wild type mice. As antigen presenting cells, when cultured with naïve T cells, bone marrow-derived macrophage from knockout mice could significantly inhibit the proliferation and activation of naïve T cell. Our studies identified a previously unknown mechanism of chronic allograft loss and pinpointed m-TOR as a molecular target in the inhibition of immune cells infiltrating and chronic rejection.