The relationships between splenic natural killer (NK) cell cytotoxicity, T and B cell function, and the development of histopathological lesions in the liver and pancreas have been studied during the course of graft-versus-host (GVH) reactions. GVH reactions were induced in (C57BL/6 X A)F1 (B6AF1) hybrids by different doses, (10,20 and 30 X 10(6)) of either parental strain C57/BL6 (B6) or A lymphoid cells. Splenic NK cell cytotoxicity was studied by employing YAC-1, an NK-cell-sensitive target. Splenic T and B cell function were assessed by mitogen responsiveness to concanavalin A, phytohemagglutinin, and Escherichia coli lipopolysaccharide, and by the in vitro plaque-forming cell response to sheep red blood cells. Histopathological lesions characteristic of GVH reactions were recognized at a time (day 8 after GVH induction) when both T and B cell functions were totally suppressed and NK cell activity was greatest. The severity of histopathological alterations later (day 16 after GVH induction) correlated with an early peak in NK cell cytotoxicity rather than with the overall NK cell activity. When low doses (10,20 X 10(6)) of B6 cells were employed to induce GVH reactions, a significant increase in NK cell activity was observed, yet neither histopathological alterations nor suppression of T and B cell functions were observed. The killing of YAC-1 targets by splenocytes obtained from the different GVH combinations could not be abrogated by pretreatment with anti-Thy 1.2 serum plus complement, suggesting that T lymphocytes were not central to this cytolytic process. These experiments demonstrated that: (1) an inverse relationship between T and B cell function and NK cell activity was observed early after GVH induction, (2) the severity of histopathological lesions and immunosuppression, as well as the degree of overall augmented NK cell activity, was determined by the dose and genotype of donor cells injected to induce GVH reactions, and (3) GVH-associated moderate-severe lesions occurred only in groups in which NK cell activity peaked early--whereas when NK cell activity peaked later, either mild or no lesions were observed, suggesting that the early rapid increase of NK cell activity may be useful for predicting the severity of GVH pathogenesis.