Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen

Abstract

Cytotoxic T lymphocytes (CTLs) are thought to detect viral infections by monitoring the surface of all cells for the presence of viral peptides bound to major histocompatibility complex (MHC) class I molecules. In most cells, peptides presented by MHC class I molecules are derived exclusively from proteins synthesized by the antigen-bearing cells 1 . Macrophages and dendritic cells also have an alternative MHC class I pathway that can present peptides derived from extracellular antigens; however, the physiological role of this process is unclear 2 . Here we show that virally infected non-haematopoietic cells are unable to stimulate primary CTL-mediated immunity directly. Instead, bonemarrow-derived cells are required as antigen-presenting cells (APCs) to initiate anti-viral CTL responses. In these APCs, the alternative (exogenous) MHC class I pathway is the obligatory mechanism for the initiation of CTL responses to viruses that infect only non-haematopoietic cells.The 'classical' MHC class I antigen-presentation pathway is thought to be the major mechanism used by the immune system to detect viral infections in all cells. In this pathway, proteins synthesized by a cell are degraded in the cytoplasm into oligopeptides, a fraction of which are transported into the endoplasmic reticulum (ER) by the transporter associated with antigen presentation (TAP). In the ER these peptides bind to new MHC class I molecules and the resulting complexes are transported to the cell surface. As MHC class I molecules must bind peptides in order to be transported to the plasma membrane, TAP is required for normal MHC class I expression at the cell surface and for antigen presentation 1 .To determine whether non-haematopoietic cells can function as APCs to initiate CTL responses to viruses, we constructed bonemarrow chimaeras by lethally irradiating C57Bl/6 mice (B6 mice; MHC class I haplotype H-2 b ) and reconstituting them with bone marrow from TAP 0/0 mice 3 (also H-2 b ; all bone-marrow chimaeras will be referred to as bone-marrow donor → irradiated recipient). As bone-marrow-derived cells in TAP 0=0 → B6 mice cannot transfer peptides from the cytosol to the ER, they are unable to use the classical MHC class I pathway 3,4 .The chimaeric mice were assayed for the generation of CTL responses following infection with wild-type vaccinia virus or with vaccinia-OVA, a recombinant vaccinia virus carrying chicken ovalbumin (OVA) as a full-length protein 5 . Although they have intact MHC class I antigen presentation in non-haematopoietic tissues, TAP 0=0 → B6 mice did not generate CTL responses to vaccinia-viral antigens (Fig. 1a) or to OVA (Fig. 1b). In contrast, robust CTL responses to these antigens were detected in control B6 → B6 mice. These results indicate that the generation of CTL responses to vaccinia virus requires bone-marrow-derived cells with functional TAP molecules.Next, we determined whether the inability of TAP 0=0 → B6 mice to generate CTL responses was due to a defect in CD8 + T cells or to a failure in antigen presenta...

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