26. Protein Presentation

In order for T cells to recognize proteins located inside of cells as antigens they must be properly "presented". What does that mean? In brief, presentation consists of two steps. First the protein must be split into fragments of the proper size. And second, the fragments have to be be positioned on the cell surface so that the T cells can interact with them. Two impressive molecular machines and a cell vacuole achieve these objectives.

The Proteasome
As I mentioned  a while back, all of our proteins are being degraded and replaced all the time. Some "turn over" faster than others. In particular, defective proteins, ones that carry errors in sequence, are particularly short lived and are chopped up into pieces rapidly. (Amazingly, I've seen several references including this one that estimate that 30 - 70% of proteins normally synthesized by cells are defective.)  Viral proteins that are made within cells also degrade quickly. There is a mechanism that I won't describe that marks these, and other, proteins for discard. But the machine that actually does the dirty work, the one that breaks the protein apart, is called a "proteasome". I show two views of proteasomes on the right. The one labelled "A" comes from a website of the U.S. Department of Energy Genome Programs. It shows a cartoon version of a proteasome caught in the act. The green snake-like line at the top is meant to represent a protein as it undergoes digestion. It enters at one end of what looks like an in-sink garbage disposal and gets cut into pieces in a hollow in the middle. Out comes protein fragments - peptides - consisting of ten to a few dozen amino acids. The second image, "B", is a portrait of the central portion of the proteasome as depicted by the molecular modelling tool, Chimera.

All human cells carry these machines inside them, but the cells of the immune system carry a modified proteasome in which some of the components have been replaced.  The protein fragments that are produced by these specialized machines are more well suited for presentation to the major histocompatibility complex.

Endosomes
What about viral proteins that haven't been synthesized in cells and are simply floating around in the extracellular  fluid? Nature has devised an entirely  different mechanism for dealing with this situation. While I wasn't aware of it, cells continually take sips of the liquid surrounding them. They enclose a tiny drop in  transfer it into their interior surrounded by a pinched off portion of the cell membrane. These vesicles, called endosomes,  that result from this action slowly change their internal composition, accumulating a host of digestive enzymes and becoming more acidic. In this way, they become capable of breaking down any proteins that may have been captured into fragments that are suitable for presentation.

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The MHC
It is the proteins of the MHC that bind these protein fragments and display them on the surface of cells so that they can be detected by T lymphocytes. But, as usual, there are some complications. For one, there are two kinds of T cells: Cytotoxic T lymphocytes and helper T lymphocytes. For another, there are two corresponding MHC's: MHC I and MHC II.

Let me tackle MHC I and cytotoxic T cells first. MHC I displays the fragments generated by the proteasome  on the surface of cells. The MHC I is ideally suited for this purpose as shown in the illustration above. The pictures were created using Chimera, the molecular modelling program that I alluded to earlier. On the left is a view of MHC I from above. The protein fragment held on a platform near the top of the molecule is clearly shown in green. It looks to me like an Incan sacrificial animal on an alter, truly a presentation to the gods. The picture on the left shows the same molecule as seen from the side. Neither view is of the complete molecule. There's an additional part of the protein that is not shown. It is located near its base. It traverses the cell membrane and extends a small segment into the cell for anchoring the MHC to the surface.

Here's the way presentation works in more detail. Proteins that are marked for destruction enter the proteasome where they are enzymatically cut into pieces. These protein fragments are transported into the endoplasmic reticulum, a network of membrane-bound sacs that occupies a good proportion of most cells. Here the MHC I proteins bind the peptides, one peptide to one MHC molecule. After a series of additional steps, the MHC-peptide complex is transported to the cell surface where it hang outs, waiting for a wandering T cell to recognize the peptide that the MHC carries. But it doesn't wait long. Old MHC/peptide complexes are constantly being degraded. New ones carrying some other peptide take their place. The process ensures that the internal protein composition of the cell is continually being sampled.

Now, I learned in graduate school that proteins bind substances with exquisite specificity. That's true of enzymes and of antibodies, for example. But the MHC's are exceptional in that they bind a wide variety of protein fragments. But not every peptide will adhere equally well. To bind to MHC I, peptides have to be about 10 amino acids long and there are some additional requirements as to which amino acids are at their ends.

There's more. I've said that each human has are six MHC I genes and therefore six corresponding MHC I proteins. Because of their diversity in sequence (there are over 1,000 MHC variants in the human population), the chances are that each of our MHC I genes specifies a different MHC protein. And, for the same reason, unrelated people will carry different MHC's. It turns out that each of these various MHC's differs in its ability to bind specific peptides, a fact that has an important consequence. If there is a viral attack on the human population, the wide range of specificities of the MHC's means that some individuals will have an MHC that can successfully bind one of the viral peptides and thereby fend off disease. Of course, that means that some people will be less able to do so.

After the MHC I rises to the cell surface it can interact with a cytotoxic T cell. I'll pursue this matter further in the next post.