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Immunodominance

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Immunodominance, 9783527312740 (3527312749), John Wiley & Sons, 2006
The normal, intact immune system does not have equal probability of responding to every potential part of a protein. It has been known for more than 50 years that only parts of the protein that are “outside” are available for antibody binding. Yet, with the advent of Western blotting techniques, antibodies that react with the interior of the protein have been routinely produced. Although not all epitopes are equally easy to produce, or are equally protective in infection, nearly any structure can be an antibody epitope.

In contrast to antibodies, T cells must recognize fragments of proteins bound to MHC molecules. In T-cell responses against viruses, very few epitopes are easily identified. In the case of LCMV, the immune response in BALB/c mice uses only a single MHC class I protein: L. K and D are not used at all. This is not because there are no suitable peptides that can bind K and D proteins, as BALB/c mice that lack L make an excellent response to LCMV. Furthermore, only a single peptide from the LCMVgenome accounts for more than 90% of the CD8 Tcells responding to infection. Because LCMV has a coding size of approximately 3500 amino acids, the immune system fixates 9 of 3500amino acids, or about 0.2%of the coding capacity.

This fixation on a small part of the potential antigenic space is not unique to LCMV in BALB/c mice. Most pathogens in inbred mice show similar immunodominance. Even in response to bacteria, where the pathogen genome size is much larger, dominance is observed. The CD8 T-cell response to Listeria monocytogenes infection is dominated by very few epitopes in both C57Bl/6 and BALB/c mice. With a genome size of almost three million base pairs, the majority of the response is restricted to two or three epitopes. The immune system is choosing only about 0.002% of the coding sequence to recognize.

Why is this so? Clearly, there are many mechanisms at work. In this volume we cover topics including (1) the mechanisms of antigen processing, i.e., how pathogen molecules are converted to molecules that are targets for cell-mediated immunity; (2) binding of processed peptides to MHC molecules, a critical step in their expression on the cell surface; and (3) the role of the pathogen itself in modifying the immune response by interfering with antigen processing and the downstream immune responses.
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