Antigen presentation to cytotoxic T lymphocytes in vivo

T he elucidation of the separate pathways of antigen presentation by MHC class II molecules to CD4 + T cells and by MHC class I molecules to CD8 + T cells has provided an understanding of how CD4 + helper responses can be directed at extracellular antigens while CD8 + cytotoxic responses can be directed against intracellular antigens. Both dass I and class II molecules are made in the endoplasmic reticulum (ER). Class II molecules travel to a post-Golgi compartment of the cell before their peptide-binding groove is charged with a tight-binding peptide. The peptides that load onto class II MHC molecules are produced in lysosomal compartments and are derived from proteins that have been endocytosed from the extracellular medium or that exist in the endosomal membrane. Newly synthesized MHC class I molecules, on the other hand, are loaded with peptides before they leave the ER. In this case, the bulk of the peptides come from cytosolic proteins that have been processed by proteasomes and transported into the ER via the specialized transporter associated with antigen processing (TAP) (1, 2). While immunologists have been aware for many years of the requirement for "specialized" or "professional" APCs to take up an extracellular antigen, degrade it, and present it to CD4 + T cells in association with MHC class II, for the most part, the requirement for such APC function in MHC class I-restricted responses has not been appreciated. There are several reasons for this lapse. MHC class I-associated peptide antigens mark the presenting cell for a lethal attack by CTLs. To avoid tissue destruction during an immune response, it is important that such marker peptides should bind almost irreversibly to the class I molecule and not be shed onto bystander cells. A second block in our understanding of antigen presentation to CTL is the difficulty in imagining how an APC can introduce foreign proteins from an infected cell into its own class I pathway. This is because there is no established pathway by which a macrophage or dendritic cell can translocate extraceUular antigens into the cytosolic processing machinery that leads to class I presentation. This leads to a major conceptual difficulty in understanding the initiaton of CTL responses to intracellular antigens. Thus, if only the pathogen-infected cell or the mutated tumor cell can present class I-associated antigen, then naive CD8 + T cells are limited to meeting antigens only at the peripheral site of infection or tumor growth. Since naive T cells do not extravasate into peripheral nonlymphoid tissues, and since many nonhematopoietic cells lack much of the costimulator function essential for T cell priming, it is clear that some mechanism must exist for presenting MHC class I-associated antigens on professional APC in the lymphoid organs. Recently, a great deal of attention has focused on the priming of class I-restricted CTL in vivo and the need for professional APCs. The existence of such a presentation pathway is highlighted in the case of a colon carcinoma cell line expressing a model CTL antigen (3). After subcutaneous inoculation of the tumor cells, only host presentation to CD8 + T cells was shown to occur. Surprisingly, there was no direct contribution by the tumor cells to the presentation of antigen for T cell priming. Presently, there is general agreement that professional antigen presentation must occur for class I-restricted responses, and a number of different forms of professional presentation have been suggested, including (a) phagocytes may possess an illdefined pathway to shunt protein from the phagosome into the cytosol, where it would enter the normal MHC class I-associated pathway of antigen processing; (b) phagocytes may digest ingested material in lysosomes and regurgitate peptides to load onto surface MHC class I; and (c) heat shock proteins (HSPs), which may normally be part of a relay team carrying proteasome-derived peptides to MHC class I, are released by dying infected or tumor cells, and these peptide carriers can access the cytosol of professional APCs. A paper in this issue by Arnold et al. (4) shows that a preparation of purified gp96 is able to prime a CD8 + T cell response to a defined CTL epitope (4). This commentary will discuss each of these mechanisms. The realization that cell-associated antigens may be presented to the immune system by professional APCs grew out of an apparent contradiction between the rules of MHC restriction of CTL recognition and the older transplantation literature. The antigens presented by target cells expressing MHC ̂ alleles are different and non-cross-reactive with the antigens presented by cells expressing MHC B. Yet it was known from transplantation studies that MHC-mismatched grafts could prime host animals for second-set rejection of test grafts from MHC-matched donors if the priming and test grafts shared the same minor histocompatibility differences from the host (5, 6). Although it was unclear from such skin graft studies that class I-restricted CD8 + T cell priming was responsible for the rapid rejection, work in short-term CTL assays established that MHC-mismatched grafts could prime CD8 + T cells specific for minor histocompatibility antigens (7), H-Y antigen (8), and SV-40 T antigen (9). The priming effect was