Although CD4(+) T cells play an important role in the regulation of allograft rejection, the exact mechanisms by which they operate and the actual contribution of direct and indirect alloreactivity pathways remain to be fully characterized. Previous studies have established a possible relationship between the indirect alloreactivity pathway and antibody production, but interpretation of these results have been complicated by shortcomings inherent to the models used in these studies. To address this issue, we have developed a model based on TCR transgenic mice derived from a CD4(+) T-cell clone which recognize specific alloantigens by both alloreactivity pathways. Skin allografts on alphabeta T-cell deficient mice adoptively transferred with transgenic CD4(+) T cells were rejected without significant delay between the two alloreactivity pathways. No IgG alloantibody was produced following allograft rejection by the direct alloreactivity pathway alone. Importantly, production of antibodies against alloantigens of the direct pathway was shown to require help from CD4(+) T cells activated by the indirect pathway. These results indicate that the events leading to the initiation of immune responses responsible for graft rejection are clearly dependent on the population of antigen-presenting cells involved in T- and B-lymphocyte activation.