Resurrecting the dead: Dendritic cells cross-present antigen derived from apoptotic cells, and induce viral- and tumor-specific cytotoxic T lymphocytes

Classically, CTLs are activated by antigens endogenously expressed by professional antigen presenting cells (APCs), processed and presented as peptide-MHC class I complexes. However, there is evidence for an exogenous pathway, whereby antigens that are not expected to gain access to the cytoplasm of an APC are indeed presented on MHC class I---the most dramatic example being the in vivo phenomenon of 'cross-priming.' My work has focused on two unanswered questions relevant to this important, but poorly defined pathway. These include the identity of the APC mediating the cross-presentation of antigen, and the mechanism whereby such antigens are acquired. We have found that human dendritic cells (DCs), but not macrophages, efficiently present antigen derived from apoptotic influenza infected cells, thus allowing for the induction of class I-restricted influenza-specific CD8+ CTLs. Interestingly, only antigenic material derived from apoptotic but not from necrotic cells are capable of charging the DCs. We have documented by immunofluorescence that it is the immature DC that is capable of efficiently engulfing apoptotic bodies/cells/corpses. And in the context of a maturation signal, these DCs will cross-present the apoptotic derived antigenic material on class I MHC leading to the induction of CD8+ T cells. While macrophages efficiently engulf apoptotic cells, they are not capable of cross-priming CTLs. This striking distinction has been correlated with the discovery that DCs and macrophages employ different receptors in the engagement and internalization of apoptotic cells.; As an in vivo example of this apoptosis-dependant exogenous pathway for loading MHC I and activating killer T cells, we investigated the mechanism by which patients with paraneoplastic cerebellar degeneration (PCD) mount an immune response to their tumors. We provide the first evidence for naturally occurring killer T-cell mediated tumor immunity in patients with ovarian and breast cancer. Additionally, we offer a mechanism by which such tumor-specific T cells might be activated---DCs capturing apoptotic tumor cells likely cross-present tumor antigen and activate tumor-specific killer T cells. This novel pathway defines a mechanism by which human DCs, a potent APC, acquire antigens from tumors, transplants, infected cells or even self tissue for the stimulation or tolerization of CTLs.