Controversy still surrounds the importance of cross-presentation versus endogenous or direct presentation of MHC-I restricted Ag in CD8(+) T-cell (T(CD8+)) immunity. It is even less clear what relative role these pathways play in shaping the T-cell repertoire specific for ubiquitous self-antigens, especially in cases where both Ag presentation pathways could potentially be involved. Here we provide evidence that a T(CD8+) repertoire specific for a determinant from the nuclear autoantigen La-SSB is largely shaped by direct presentation. In this system, mouse T(CD8+) reactive to a xenogeneic human La (hLa(51-58)) K(b) peptide did not recognize directly presented peptide on either spleen cells from hLa-Tg mice or hLa transfected syngeneic cells. Interestingly, the same T(CD8+) were activated by in vivo challenge with allogeneic APC expressing either the Tg hLa or loaded with intact recombinant hLa protein, indicating functional cross-presentation of the hLa(51-58). However, in irradiated bone marrow chimeric mice, DC expressing Tg hLa, but not WT DC that matured in hLa-Tg mice, constitutively presented the hLa(51-58) to T(CD8+). These data demonstrate that although both the direct- and cross-presentation pathways are potentially operative in revealing hLa(51-58) to T(CD8+), the T(CD8+) repertoire to this determinant is shaped quantitatively according to the efficiency of Ag presentation.