Mature B lymphocytes secrete antibodies in great quantity into the blood stream. In aggregate they are capable of synthesizing proteins that are capable of binding to and dealing with almost any molecular intruder. But they have one great limitation: they can't see inside of cells. Antibodies can bind to the surface of foreign microbes, but when invaders, like viruses, penetrate the cell membrane and take up residence within, they are hidden from attack. Evolution has, of course, devised an appropriate solution. It has developed the second arm of the adaptive immune system: cellular immunity. The major players in this process are two kinds of T lymphocytes, so named because they mature in the thymus rather than the bone marrow.
T and B lymphocytes share many properties but also exhibit considerable differences. One critical distinction between the two cell types is that T cells don't secrete antibodies. In fact, T cell don't make antibodies at all. However, like B cells they have receptors that have constant and variable regions that derive from genes whose segments have been randomly rearranged during their development. Utilizing this mechanism, millions of T cell clones are generated, each bearing a different receptor. Because of the great diversity of binding sites in the T cell population, it would seem like T lymphocytes would be capable of recognizing many different molecules. Well, they do and they don't. T cells are specialists. They can't bind to molecules just floating in the blood. What's more, they're restricted to the kinds of molecules to which they can bind. They only (with a few exceptions) recognize small fragments of proteins. And only protein pieces that are properly "presented" to them, meaning that they only can bind peptides that are in the grasp of a special apparatus on the surface of another cell. I'll begin this post on cellular immunity with a short description of the gene that specify the proteins that act as the presenters, MHC I and MHC II. In the next post, I'll tackle the presentation mechanism itself.
MHC - Genes
I wrote briefly about the major histocompatibility complex in a previous post in connection with the natural killer cells of the innate immune system. Because the MHC plays a much bigger role in the workings of T cells, I'll expand upon my previous discussion here.
The MHC refers to two entities, and the distinction is not always clearly noted. First, there are the MHC proteins, a subject that I'll get into in the next post. And second, there is the region of the sixth human chromosome that codes for them - the major histocompatibility complex. As a geneticist, I was surprised to learn that the chromosomal MHC spans an enormous distance, some three million five hundred base pairs. That's nearly the size of an average bacterial genome! Located in this region are over 200 genes, about half having a known function in immunity (the role of many has not yet been determined). The location of the six MHC genes and several others are shown in the figure above. Notice that three of these genes specify the MHC I proteins (in blue), and three the MHC II's (in yellow).
Perhaps the most intriguing property of the MHC I and II genes is their enormous variation in sequence. Of course that's reflected in the proteins they code for as well. I've already written about the variation in antibody genes and T cell receptor genes. But the variety of the MHC's is a different story. Because we inherit two six sixth chromosomes (one from our mother and one from our father), we humans have 12 MHC genes in all. We're born with these genes and, unlike antibody genes, we retain the same sequence and number throughout our lives. The variation that I'm writing about occurs within the human population. That is, if you were to determine the sequence of the MHC genes in thousands of unrelated individuals, the probability is that few would be the same.
Now to be clear, almost all genes show variability from person to person. For example, there are about 1,000 known variants in the beta hemoglobin genes (yes, there's more than one) within the human population. But most of these differences in DNA sequence are rare. Most people bear only one form of the gene. The MHC genes are different. More than 10,000 variants are known, and they're widely distributed among the populace. According to Abbas et al., the MHC genes are the most variable found in "any mammalian genome".
What intrigues me as a geneticist is how this variability is maintained. In most cases, if a change of sequence occurs in a gene – a mutation – it will either be more favorable than the existing sequence or not. If so, it will tend to replace the existing gene in the population over time, eventually becoming the dominant form. If not, it will be selected against and tend to disappear. (There may, of course, be mutations that are neutral, neither favorable or harmful. These will replace the prexisting gene at a random rate partially dependent on how often they appear in the population). This maintenance of enormous variability almost certainly has to do with what the MHC proteins do and how they do it, subjects that I'll take up in the next post.