Processing of Antigen Is Required for Recognition by T Cells

The results obtained by K. Ziegler and E. R. Unanue were among those that contradicted the prevailing dogma that antigen recognition by B and T cells was basically similar. These researchers observed that TH-cell activation by bacterial protein antigens was prevented by treating the antigen-presenting cells with paraformaldehyde prior to antigen exposure. However, if the antigen-presenting cells were first allowed to ingest the antigen and were fixed with paraformaldehyde 1-3 h later, TH-cell activation still occurred (Figure

8-3a,b). During that interval of 1-3 h, the antigen-presenting cells had processed the antigen and had displayed it on the membrane in a form able to activate T cells.

Subsequent experiments by R. P. Shimonkevitz showed that internalization and processing could be bypassed if antigen-presenting cells were exposed to peptide digests of an antigen instead of the native antigen (Figure 8-3c). In these experiments, antigen-presenting cells were treated with glu-taraldehyde (this chemical, like paraformaldehyde, fixes the cell, making the membrane impermeable) and then incubated with native ovalbumin or with ovalbumin that had been subjected to partial enzymatic digestion. The digested ovalbumin was able to interact with the glutaraldehyde-fixed antigen-presenting cells, thereby activating ovalbumin-specific TH cells, whereas the native ovalbumin failed to do so. These results suggest that antigen processing involves the digestion of the protein into peptides that are recognized by the ovalbumin-specific TH cells.

EXPERIMENTAL CONDITIONS

T-CELL ACTIVATION

EXPERIMENTAL CONDITIONS

Antigen Presenting Cell Ovalbumin

Th cell

Experimental demonstration that antigen processing is necessary for TH-cell activation. (a) When antigen-presenting cells (APCs) are fixed before exposure to antigen, they are unable to activate TH cells. (b) In contrast, APCs fixed at least 1 h after antigen exposure can activate TH cells. (c) When APCs are fixed

Th cell

FIGURE 8-3

Experimental demonstration that antigen processing is necessary for TH-cell activation. (a) When antigen-presenting cells (APCs) are fixed before exposure to antigen, they are unable to activate TH cells. (b) In contrast, APCs fixed at least 1 h after antigen exposure can activate TH cells. (c) When APCs are fixed before antigen exposure and incubated with peptide digests of the antigen (rather than native antigen), they also can activate TH cells. TH-cell activation is determined by measuring a specific TH-cell response (e.g., cytokine secretion).

Antigen-presenting cells

Professional antigen-presenting cells

Nonprofessional antigen-presenting cells

Dendritic cells (several types) Macrophages B cells

Fibroblasts (skin) Glial cells (brain) Pancreatic beta cells

Thymic epithelial cells Thyroid epithelial cells Vascular endothelial cells

At about the same time, A. Townsend and his colleagues began to identify the proteins of influenza virus that were recognized by TC cells. Contrary to their expectations, they found that internal proteins of the virus, such as matrix and nucleocapsid proteins, were often recognized by TC cells better than the more exposed envelope proteins. Moreover, Townsend's work revealed that TC cells recognized short linear peptide sequences of the influenza protein. In fact, when noninfected target cells were incubated in vitro with synthetic peptides corresponding to sequences of internal influenza proteins, these cells could be recognized by TC cells and subsequently lysed just as well as target cells that had been infected with live influenza virus. These findings along with those presented in Figure 8-3 suggest that antigen processing is a metabolic process that digests proteins into peptides, which can then be displayed on the cell membrane together with a class I or class II MHC molecule.

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