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Although CD154 costimulation blockade prolongs allograft survival in multiple transplantation models, the underlying immunological mechanisms remain to be elucidated.We used a murine orthotopic kidney allograft (KTx) model to analyze the impact of CD154 blockade on trafficking and function of alloreactive T effector versus T regulatory cells. A single dose of MR1 Ab treatment at the time of KTx significantly improved the survival of Balb/c KTx in naïve C57BL/6 recipients (mean survival time >100 days vs. 52 days in controls; P<0.005), and improved graft histology, as evidenced by decreased lymphocyte infiltration and preservation of tissue architecture (days 6–8). In the early posttransplant phase, fluorescence-activated cell sorting analysis revealed preferential depression of T effector (CD8+CD25+) and relative enrichment of T-regulatory (CD4+CD25+CD152+) cells selectively in KTx. This pattern was further supported by intragraft gene expression analysis, which showed increased FoxP3/Tbet ratio and simultaneously decreased granzyme B/IFN-γ levels in Ab-treated recipients. Additionally, MR1 Ab selectively up-regulated intragraft CCL17, but suppressed CXCL9/CCL5, in parallel with increased CCR4/CCR8 but unaltered CXCR3 expression.These results provide evidence, at both cellular and molecular levels, that CD154 blockade in murine KTx recipients differentially targeted T-effector and T-regulatory cell subsets by regulating intragraft induction of chemokines targeting distinct T-cell subsets.