Antigen Presentation Pathways to Class I and Class II MHC‐Restricted T Lymphocytes

Our observations on the cellular immune response to type-A influenza suggest the existence of two distinct pathways of protein antigen presentation to T lymphocytes. One of these pathways is involved with presentation of antigens introduced into the presenting cell from without. This exogenous presentation pathway is the well-recognized route of presentation of soluble and particulate antigens to T lymphocytes. This pathway probably involves uptake of antigen into endocytic vesicles, alteration of antigen within an intracellular compartment, and subsequent display of antigen on the presenting cell surface (Unanue 1984). The second pathway is one which we have tentatively designated as an endogenous presentation pathway. The constraints on this pathway have yet to be fully defined. At a minimum, this pathway appears to involve the presentation of antigens which are synthesized de novo in the presenting cell utilizing the cell's biosynthetic machinery. This pathway may also handle preformed antigens located within the cytosolic compartment of the presenting cell. Perhaps the most striking feature of these two antigen presentation pathways is the close association between the MHC restriction of an antigen-specific T lymphocyte and the pathway of antigen presentation to that T lymphocyte. Our data suggest that this association holds both at the effector level and at the level of induction of T lymphocytes. Thus, presentation of a given antigen by the endogenous pathway preferentially triggers a response from class I MHC-restricted T lymphocytes directed to that antigen. The molecular basis for this link of class I MHC-restriction to the endogenous pathway and MHC class II restriction to the exogenous pathway is unknown. It seems likely that interactions between MHC molecules and antigen within the presenting cell may be critical for the demarcation of these pathways. Thus, for example, antigen presented by the endogenous route may only be able to associate intracellularly with newly synthesized or recycling class I MHC molecules. An understanding of the molecular basis of this phenomenon will require detailed information on the expression, intracellular trafficking, and transport of class I and class II MHC molecules in the antigen-presenting cell. An unresolved issue, at least in the case of viral antigens, is the nature and form of the antigenic moieties presented by the exogenous and endogenous pathways. In the case of viral antigen presentation to class II MHC-restricted T lymphocytes, there is strong, albeit indirect, evidence for processing of antigen and recognition of fragments of viral polypeptides (Lamb et al. 1982, Hackett et al. 1983).(ABSTRACT TRUNCATED AT 400 WORDS)