A significant increase in the expression and activity of tissue transglutaminase (tTG), one of the effector elements of apoptosis, was observed during involution of thymus elicited by treatment with either anti-CD3 antibody or dexamethasone or by irradiation. The blood plasma concentration of epsilon(gamma-glutamyl)lysine isodipeptide, the end-product of the digestion of transglutaminase cross-linked proteins, was also elevated in each of these cases. tTG was localized in cells of the cortical layer of the thymus and immunofluorescence double staining revealed that the enzyme appeared in the apoptotic cells. None of these observations could be made when apoptosis was induced by fas-receptor stimulation. The lack of tTG activity in fas-stimulated cells was accompanied with a less organized apoptotic morphology. Our data suggest that distinct signalling pathways, which induce apoptosis within the same cell type, can differentially regulate the expression of tTG, and this enzyme may be involved in structural stabilization of the apoptotic cells.