On the site and mode of antigen presentation for the initiation of clonal expansion of CD8 T cells specific for a natural tumor antigen

Because of the low frequency of antigen-specific T cells, early events in t he activation of tumor-specific T cells in vivo have not been well characte rized. There is still no direct documentation on where the clonal expansion begins and how tumor antigens are presented to the host CD8 T cells to ini tiate it. Here we used transgenic T cells specific for a natural tumor anti gen PIA to evaluate the kinetics. location, and modes of antigen presentati on for initiating CTL response in vivo. Our results demonstrate that the in itial activation of PIA-specific T cells takes place in the lymphoid organs . The activated T cells then migrate into tumors, where they undergo accele rated division and acquire distinct activation markers. The site of initiat ion cannot be altered by either local expression of costimulatory molecules or by intratumor injection of naive T cells. Moreover, using genetic model s that allow only one mode of antigen presentation, we show here that both cross-presentation of PIA by the host antigen-presenting cells. and direct antigen presentation and costimulation by the tumor cells are sufficient to initiate rapid T cell-clonal expansion in the lymphoid organ. These result s provide direct evidence for two fundamental assumptions on the mechanisms of T-cell activation in vivo.