Time-related and dose-related popliteal lymph node (PLN) enlargement and lymphocyte subset alterations owing to subcutaneous (s.c.) injection of streptozotocin (STZ) into the foot pad were determined in (C57BL/6 x DBA/2)F1 [B6D2F1] mice. Early cell activation and time-related changes in T and B lymphocyte subsets were monitored during the onset of STZ-induced lymphoproliferative reaction by flow cytometry and immunophenotyping of lymphocyte subsets stained with a panel of monoclonal antibodies. Examination of cell size and chromatin decondensing for T and B cell subsets revealed differences in their activation profiles during the early phase of STZ-induced lymph node enlargement. The kinetics of the reaction showed initial activation and proliferation of CD4+ cells associated with accumulation of CD8+ and B cells. Subsequently CD8+ cells were activated and proliferated, but there was no evidence of early or late B cell activation as shown by the lack of increase in cell size or nuclear decondensation and the low and transient synthesis of immunoglobulins. The activation characteristics for CD4+ and CD8+ cell subsets in STZ-induced node enlargement were found to be analogous with T cell activation in acute allogeneic graft-versus-host (GVH) reaction in which the F1 recipient differed from the parent at both class I and II MHC loci. Our data support a central role for T cell activation in the induction of STZ-related PLN enlargement and suggest that recirculatory host B cells can play a major role in early node enlargement.