Comments and Answers The Interplay between MHC Peptide TCR and T cell selection or activation

Before we knew so much about what was happening at the molecular level, experimental data from diverse in-vivo and in-vitro experimental systems was a bit confusing. But it became obvious that genetic differences in what was called the Major Histocompatibility Complex (MHC) could not only result in strong tissue graft rejection, but could also determine whether an individual could mount an immune response to a particular antigen. This was most strikingly demonstrated in studies with inbred animals in which the pair of MHC-bearing chromosomes were identical within the MHC region. Furthermore, differences in MHC could determine whether virally infected cells from one individual could be killed by cytotoxic cells raised against the virus in another individual, or whether T lymphocytes from an individual previously immunized with antigen could mount a proliferative secondary response to the same antigen presented by cells (APC) from another individual.

Other work clearly demonstrated that for T cells to respond to complex antigens (a small protein like cytochrome C or lysozyme from another species is complex enough) not only must the antigen be "presented" by APCs, but also the antigen had to be "processed" by the APCs.

We now know that the processing involves digestion of the protein into relatively short polypeptide fragments, a few of which are capable of being firmly bound by newly assembling MHC class I or class II cell surface proteins.

Knowledge of the molecular structures of the MHC molecules and T cell receptor, and knowledge of some critical components of the antigen presentation machinery now allows us to understand the process much better by thinking of what is happening at the molecular level.

In doing so, it is useful to start thinking quite generally about how proteins interact with each other. The approach will be quite descriptive; we will not get into any deep physical, chemical or mathematical theory, so don't shy away.

The discussion proceeds through the following headings:

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