Origin of the Many Clones of Lymphocytes

Origin of the Many Clones of Lymphocytes

Only several hundred to a few thousand genes code for the millions of different types of antibodies and T lymphocytes. At first, it was a mystery how it was pos-sible for so few genes to code for the millions of dif-ferent specificities of antibody molecules or T cells that can be produced by the lymphoid tissue, especially when one considers that a single gene is usually nec-essary for the formation of each different type of protein. This mystery has now been solved.

The whole gene for forming each type of T cell or B cell is never present in the original stem cells from which the functional immune cells are formed. Instead, there are only “gene segments”—actually, hundreds of such segments—but not whole genes. During prepro-cessing of the respective T- and B-cell lymphocytes, these gene segments become mixed with one another in random combinations, in this way finally forming whole genes.

Because there are several hundred types of gene segments, as well as millions of different combinations in which the segments can be arranged in single cells, one can understand the millions of different cell gene types that can occur. For each functional T or B lym-phocyte that is finally formed, the gene structure codes for only a single antigen specificity. These mature cells then become the highly specific T and B cells that spread to and populate the lymphoid tissue.

Mechanism for Activating a Clone of Lymphocytes Each clone of lymphocytes is responsive to only a single type of antigen (or to several similar antigens that have almost exactly the same stereochemical characteristics). The reason for this is the following: In the case of the B lymphocytes, each of these has on the surface of its cell membrane about 100,000 antibody molecules that will react highly specifically with only one specific type of antigen. Therefore, when the appropriate antigen comes along, it immediately attaches to the antibody in the cell membrane; this leads to the activation process, which we describe in more detail subsequently. In the case of the T lymphocytes, molecules similar to antibodies, called surface receptor proteins (or T-cell markers), are onthe surface of the T-cell membrane, and these, too, are highly specific for one specified activating antigen.

Role of Macrophages in the Activation Process. Aside fromthe lymphocytes in lymphoid tissue, literally millions of macrophages are also present in the same tissue. These line the sinusoids of the lymph nodes, spleen, and other lymphoid tissue, and they lie in apposition to many of the lymph node lymphocytes. Most invad-ing organisms are first phagocytized and partially digested by the macrophages, and the antigenic prod-ucts are liberated into the macrophage cytosol. The macrophages then pass these antigens by cell-to-cell contact directly to the lymphocytes, thus leading to activation of the specified lymphocytic clones. The macrophages, in addition, secrete a special activating substance that promotes still further growth and reproduction of the specific lymphocytes. This sub-stance is called interleukin-1.

Role of the T Cells in Activation of the B Lymphocytes. Mostantigens activate both T lymphocytes and B lympho-cytes at the same time. Some of the T cells that are formed, called helper cells, secrete specific substances (collectively called lymphokines) that activate the specific B lymphocytes. Indeed, without the aid of these helper T cells, the quantity of antibodies formed by the B lymphocytes is usually slight. We will discuss this cooperative relationship between helper T cells and B cells again after we have an opportunity to describe the mechanisms of the T-cell system of immunity.