A Guide to Understand the Clonal Selection Theory

The idea of clonal selection was first put forth by Niels Jerne in 1955. It was later officially outlined and explained in detail by the immunologists Sir Frank Macfarlane and David Talmage in 1957.

Clonal selection theory is an important scientific theory in immunology that explains how the immune system generates specific antibodies against invading antigens, during an immune response.

This theory is now considered a fact based on the abundant experimental proof provided by various scientists since its conception. It has now become the foundation of molecular immunology, helping to explain the process and phenomenon of acquired or adaptive immunity.

A vague theory of specific antibody production was proposed by Paul Ehrlich in 1900. According to this theory, the antigen was thought to bind to a complementary membrane-bound antibody. This binding would cause the cell to activate intensive synthesis and secretion of that antibody. 

Later, in 1955, Niels Jerne improved on this theory by hypothesizing that serum already consists of various different types of antibodies prior to any infection, and on interaction with the antigen, the 'specific' binding antibody is mass produced.

In 1957, David Talmage further proposed that each antibody-presenting cell synthesizes only one type of antibody. Later that same year, Sir Frank Macfarlane put forth a theory suggesting that the antibody selection occurs via clonal selection, where two types of clones were generated by the cell; one for memory and the other for antibody production.

Later in 1958, Gustav Nossal and Joshua Lederberg provided the first experimental evidence that proved this theory by showing that each B lymphocyte cell produces only one type of antibody.

• The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical specificity as the parental cell.
• Lymphocytes bearing receptors for self molecules will be detected and deleted at an early stage.

❖ At any given time in a lymph node, lymphocytes are being produced by lymphoid progenitor stem cells. These cells produce immature lymphocytes, each of which display unique specific receptors.

While each cell has only one type of receptor, a vast diversity of such cells are produced so as to have a wide variety of possible antibodies prior to the occurrence of any infection. This diversity is obtained by the somatic hypermutation of the antibody-coding genes that result in varying V(D)J combinations.

The other lymphocytes undergo maturation in different parts of the body. The ones which mature in the thymus gland are called T cells (includes helper T cells and cytotoxic T cells), and those that mature in the bone marrow are called B cells. These cells are inactive, but get activated during an immune response.

Each antigen has certain surface molecules, called epitopes. When an antigen gains entry into the body by crossing the skin barrier, the first cells it encounters are leukocytes and dendritic cells which recognize the antigens, determine its foreign nature, and then engulfs them.

❖ After the antigen has been engulfed, the leukocytes digest them and display the antigen epitopes on their cell surface. These antigen presenting cells (APC) then migrate along the lymphatic vessels of the body till they reach a lymph node, where they interact with naive B and T lymphocytes.

These lymphocytes selectively bind to the antigenic epitopes on the leukocytes' cell surface. This way, B cells, cytotoxic T cells, and helper T cells are selected. This selection is clonal in nature as specific cells are chosen from a pool of their clones bearing different receptors.

❖ The selective binding of the helper T, cytotoxic T, and B cell receptors to the epitope displayed by the leukocyte, cause these 3 types of cells to undergo activation. The helper T cells have a synergistic effect on the cytotoxic T cells and the B cells and help them to divide rapidly.

❖ During multiplication, the cytotoxic T cells and the B cells undergo differentiation, and the differentiated cells undergo clonal expansion, which refers to formation of multiple identical copies of the same cell. The T cells differentiate into T killer cells and T killer memory cells, while the B cells differentiate into plasma cells and B memory cells.

❖ The T killer cells function to seek and destroy any infected cells, while the T killer memory cells act as a cytotoxic memory cell. The plasma cells rapidly produce and secrete antibodies into the serum, to help with antigen detection.

The B memory cells act as a stored memory for plasma cell. The memory cells stay in the system for years, whereas the other cells degrade and perish within a short time. In the event of a second attack by the same antigen, these memory cells undergo rapid cloning into plasma and T killer cells to deter the infection.

❖ The recording of antigen response in the form of memory cells is called immunological memory. The first immunogenic response to an antigen is called a primary response, and it takes almost one week to produce a soluble, specific antibody. A second response elicited by the same antigen is called secondary response which calls the memory cells into action.

During a repeated attack by the same antigen, the immune response is immensely faster and produces an exponentially higher amount of antibodies. In addition, the antibody binding affinity and specificity also shows an almost 10,000 fold increase. Hence making the second immune response more efficient and prompt.

The major application of the clonal selection theory is in production of monoclonal antibodies that can be utilized for cancer treatment, tissue transplant typing, and purification of industrially-produced biological products.

Specific antibodies are also used in diagnostic tests like the ELISA (Enzyme-Linked Immunosorbent Assay) test that is used to detect HIV infection. In addition, the immunological memory produced as a result of clonal selection forms the rationale behind vaccination.