Cytotoxic T lymphocytes (CTL) are important effectors of immunity to pathological conditions such as microbial infections and cancer in that they have the ability to destroy “abnormal” cells such as those infected by intracellular pathogens or tumor cells. CTL recognize these abnormal cells as “foreign” via cell-surface antigen-specific T cell receptors (TCR), which bind to antigenic peptide epitopes complexed with major histocompatibility complex (MHC) molecules (most commonly MHC class I molecules) on the surface of the abnormal cells. CTL peptide epitopes are generally derived from intracellular proteins such as microbial (e.g., viral) proteins and tumor-associated antigens that are: (i) synthesized within the cell; (ii) proteolytically processed within the cell; and (iii) transported by the TAP transporter molecules into the endoplasmic reticulum (ER) [Germain et al. (1994) Cell 76:287; York et al. (1996) Annual Review of Immunology 14:369; Heemels et al. (1995) Annu Rev Biochem 64:463; Momburg et al. (1998) Adv Immunol 68:191]. Once in the ER, the CTL peptide epitopes can be further “trimmed” by the action of peptidases into an optimal size for association with MHC class I molecules; after complexing of CTL peptide epitopes with an appropriate MHC class I molecule, the resulting complex is exported to the cell-surface where it is available for recognition by a relevant TCR [Snyder et al. (1994) J Exp Med 180:2389; Roelse et al. (1994) J Exp Med 180:1591; Mo et al. (1999) J Immunol 163:5851; Paz et al. (1999) Immunity 11:241; Powis et al. (1996) Immunity 4:159; Yewdell et al. (2001) Curr Opin Immunol 13:13]. This process is known as the “MHC class I antigen-processing pathway.”
The requirement for intracellular processing of antigens creates some constraints on the ability to induce CTL responses using exogenous, non-infectious vaccines such as killed pathogens or protein antigens. These constraints arise because cells, e.g., antigen presenting cells (APC), are generally not very efficient at processing via the MHC class I antigen-processing pathway antigens that are not synthesized within the cell but are imported into the cell by any of the mechanisms by which such importation occurs.