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The main stimulus triggering early acute allograft rejection is known to be delivered by the allogeneic “passenger” leukocytes present within the grafts. Once these cells have been replaced by cells of recipient origin, subsequent rejection episodes are generally less frequent and less acutely destructive. How this replacement affects the cell populations responsible for allograft rejection is not known. Here we report that rat alloreactive non‐cytotoxic AS (RT1¹) anti‐August (RT1^C) CD4⁺ T cells, that were shown to be specific for RT1.B^C+ August spleen stimulators, were able to cause acute rejection of normal August kidney allografts transplanted into sublethally irradiated AS recipients. These cells, however, failed to reject passenger cell‐depleted (PCD) August kidneys, despite the substantial expression of RT1.B^C+ products on the graft tubular epithelium. In experiments in vitro, August kidney tubular epithelial cells …