Evidence for Two Processing and Presentation Pathways

The immune system uses two different pathways to eliminate intracellular and extracellular antigens. Endogenous antigens (those generated within the cell) are processed in the cy-tosolic pathway and presented on the membrane with class I MHC molecules; exogenous antigens (those taken up by en-docytosis) are processed in the endocytic pathway and presented on the membrane with class II MHC molecules (Figure 8-4).

Experiments carried out by L. A. Morrison and T. J. Braciale provided early evidence that the antigenic peptides presented by class I and class II MHC molecules are derived from different processing pathways. These researchers based their experimental protocol on the properties of two clones of TC cells, one that recognized influenza hemagglutinin (HA) associated with a class I MHC molecule, and an atypical TC line that recognized the same antigen associated with a class II MHC molecule. (In this case, and in some

CYTOSOLIC PATHWAY

Endogenous antigens

-7 Cytoplasmic proteasome complex

Peptides —^^ Endoplasmic ■ reticulum

""^Peptide-class I MHC complex

Exopeptidases Amino acids

ENDOCYTIC PATHWAY

Exogenous -

antigens Endocytosis or phagocytosis sP

Endocytic compartments -

Peptides

Peptide-class II MHC complex

FIGURE 8-4

Overview of cytosolic and endocytic pathways for processing antigen. The proteasome complex contains enzymes that cleave peptide bonds, converting proteins into peptides. The antigenic peptides from proteasome cleavage and those from endocytic compartments associate with class I or class II MHC molecules, and the peptide-MHC complexes are then transported to the cell membrane. TAP (transporter of Antigenic peptides) transports the peptides to the endoplasmic reticulum. It should be noted that the ultimate fate of most peptides in the cell is neither of these pathways, but rather to be degraded completely into amino acids.

others as well, the association of T-cell function with MHC restriction is not absolute). In one set of experiments, target cells that expressed both class I and class II MHC molecules were incubated with infectious influenza virus or with UV-inactivated influenza virus. (The inactivated virus retained its antigenic properties but was no longer capable of replicating within the target cells.) The target cells were then incubated with the class I-restricted or the atypical class II-restricted TC cells and subsequent lysis of the target cells was determined. The results of their experiments, presented in Table 8-2, show that the class II-restricted TC cells responded to target cells treated with either infectious or noninfectious influenza virions. The class I-restricted TC cells responded only to target cells treated with infectious virions. Similarly, target cells that had been treated with infectious influenza virions in the presence of emetine, which inhibits viral protein synthesis, stimulated the class II-restricted TC cells but not the class I-restricted TC cells. Conversely, target cells that had been treated with infectious virions in the presence of chloroquine, a drug that blocks the endocytic processing pathway, stimulated class I- but not class II-restricted TC cells.

These results support the distinction between the processing of exogenous and endogenous antigens, including the preferential association of exogenous antigens with class II MHC molecules and of endogenous antigens with class I

Effect of antigen presentation on activation of class I and class II MHC-restricted TC cells

CTL ACTIVITYt

Treatment of target cells" Infectious virus

UV-inactivated virus (noninfectious) Infectious virus + emetine Infectious virus + chloroquine

Class I restricted

Class II restricted

"Target cells, which expressed both class I and class II MHC molecules, were treated with the indicated preparations of influenza virus and other agents. Emetine inhibits viral protein synthesis, and chloroquine inhibits the endocytic processing pathway.

'Determined by lysis (+) and no lysis (—) of the target cells.

SOURCE: Adapted from T. J. Braciale et al., 1987, Immunol. Rev. 98:95.

MHC molecules. Association of viral antigen with class I MHC molecules required replication of the influenza virus and viral protein synthesis within the target cells; association with class II did not. These findings suggested that the peptides presented by class I and class II MHC molecules are trafficked through separate intracellular compartments; class I MHC molecules interact with peptides derived from cy-tosolic degradation of endogenously synthesized proteins, class II molecules with peptides derived from endocytic degradation of exogenous antigens. The next two sections examine these two pathways in detail.

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