Dendritic cells in the kidney take up antigens, but little is known about their role in providing co-stimulatory signals for the activation of CD4(+) cells. This study examined the phenotype of dendritic cells in the renal interstitium and in the lymph node draining the kidney before and after intrarenal ovalbumin injection. After intrarenal injection of the antigen, expression of the co-stimulatory molecules CD86 and programmed cell death ligand 1 (PD-L1) increased on renal dendritic cells, whereas expression of only CD86 increased on dendritic cells of the draining lymph node. The activation and proliferation of antigen-specific CD4(+) cells in the lymph node were assessed by transfer of naive, fluorescently labeled ovalbumin-specific T cell receptor transgenic cells to mice before antigen administration. Blocking both CD86 and CD80 profoundly inhibited CD4(+) cell proliferation, but CD86 was the dominant CD28 ligand in the early proliferative response of CD4(+) cells. Conversely, activation of PD-1, the receptor expressed on CD4(+) cells that binds PD-L1 and PD-L2, reduced the proliferation of CD4(+) cells in the draining lymph node. Comparing subcutaneous and intrarenal administration of antigen, it was found that CD4(+) cell activation was slower and the effects of combined CD80 and CD86 blockade were more profound when antigen was presented via the kidney compared with the skin. In summary, renal dendritic cells take up antigen and participate in the control of antigen-specific CD4(+) cell proliferation by upregulating co-stimulatory molecules such as CD86 that stimulate CD4(+) cell proliferation and by signaling through PD-1, which prevents an inappropriately exuberant immune response.