MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I-RESTRICTED CROSS-PRESENTATION IS BIASED TOWARDS HIGH-DOSE ANTIGENS AND THOSE RELEASED DURING CELLULAR DESTRUCTION

Naive T cells recirculate mainly within the secondary lymphoid compart ment, but once activated they can enter peripheral tissues and perform effector functions. To activate naive T cells, foreign antigens must traffic from the site of infection to the draining lymph nodes, where they can be presented by professional antigen presenting cells. For ma jor histocompatibility complex class I-restricted presentation to CD8( +) T cells, this can occur via the cross-presentation pathway. Here, w e investigated the conditions allowing antigen access to this pathway. We show that the level of antigen expressed by peripheral tissues mus t be relatively high to facilitate cross-presentation to naive CD8(+) T cells. Below this level, peripheral antigens did not stimulate by cr oss-presentation and were ignored by naive CD8(+) T cells, although th ey could sensitize tissue cells for destruction by activated cytotoxic T lymphocytes (CTLs). Interestingly, CTL-mediated tissue destruction facilitated cross-presentation of low dose antigens for activation of naive CD8(+) T cells. This represents the first in vivo evidence that cellular destruction can enhance access of exogenous antigens to the c ross-presentation pathway. These data indicate that the cross-presenta tion pathway focuses on high dose antigens and those released during t issue destruction.