Clonal Proliferation


 Here we have a population of mature B-cells containing antigen receptors, and educated T-cells with T-cell antigen receptors on their surfaces. At any one time in a population of lymphocytes there will be millions of different clones of cells each carrying a different receptor, and therefore only able to recognise a particular type of antigen.

This means that in a normal immune system there is always a small sub-population of cells which are able to recognise a specific antigen. If this were not the case, the human race would have long since died out. Such cells are said to share the same specificity. This is one of the reasons why lymphocytes circulate around the body to ensure that the small number of cells which are able to recognise a specific antigen will actually come into contact with it.

Consequently, most of the cells in the human body are never called upon to fight infection. They are simply there just in case they are needed to combat any new strains of pathogen that might enter the host.

We are going to look at how B-cells and T-cells differentiate and the mechanisms which bring this about.

    Here we have a virgin lymphocyte pool. In the presence of an antigen only one of these many different B-cells is able to bind to that antigen successfully. This process known as clonal selection initiates a primary immune response which causes the cell to undergo a series of irreversible changes.

     The antigen is taken up from solution by the B-cell's surface immunoglobulin. It is internalised and processed.

   Antigen fragments are subsequently re-expressed on the B-cell surface associated with MHC class 2 molecules for presentation to TH2 cells. Receptors for interleukin 4 are also induced on the B-cell.

    Presentation of the antigen to the TH2 cell causes vesicles within the T-cell to fuse with the cell surface and release cytokines, including interleukin 4, which then binds to the interleukin 4 receptors on the B-cells.

   This then activates the B-cell triggering its division.

   Other cytokines released from the TH2 cell including interleukin 2, interleukin 4, interleukin 5, and interleukin 6 then bind to the appropriate receptors on the B-cells, causing them to differentiate.

   Some of the cells become plasma cells which produce a secreted form of the original antibody. Consequently they are also known as AFC's or antibody forming cells.

The antibody produced is used to facilitate further phagocytosis by the macrophages which are able to use it as an adaptor to bind to the antigen.

Plasma cells are a different shape from B-cells and have lost all their original cell surface antibody. They will go on dividing several times but within days or weeks they will die.

     Other cells become memory cells. They have undergone a series of phenotypic changes making them more efficient at reacting to the same antigen, if it is ever presented again in the future. This means that there is always a ready supply of cells with the appropriate specificity to fight infection. These cells can live for many years, and this increased efficiency of the memory cells to fight infection underlies the enhanced secondary immune response. Memory cells confer lasting immunity against a pathogen, which is the basic principle behind vaccination.

   Now we shall look at how T-cells differentiate. The process is quite similar.

   Again we have a pool of virgin lymphocytes. There are millions of different clones of T-cells, each carrying a different T-cell antigen receptor.

In the presence of an antigen-presenting cell such as a macrophage, only one of these many different T-cells is able to bind to that antigen successfully. As we have seen, this is called clonal selection.

    The antigen-presenting cell interacts with the T-cell and releases cytokines such as interleukin 1, which cause the expression of interleukin 2 receptors on the surface of the T-cell. There are also crucial interactions between pairs of co-stimulatory molecules on the surfaces of each of the two cells.

   In addition to being able to bind interleukin 2 using its new receptor, the T-cell is now also able to produce its own interleukin 2 enabling it to stimulate itself.

This ability to produce cytokines which can act on cells of the type that produced them is called an autocrine action, whereas producing cytokines which stimulate another cell type is a paracrine action.

   These interleukin 2 cytokines bind to the receptors on the surface of the T-cell triggering division. This causes the induction of new co-stimulatory molecules onto the surface of the T-cell.

   The T-cell divides, and after five or six cycles there is a gradual loss of the interleukin 2 receptor. This prevents the cells from receiving any positive signals to continue dividing.

    All of the T-cells eventually lose their interleukin 2 receptors but retain their T-cell antigen receptor. However, some of them also retain the signalling co-stimulatory molecules and those become the memory T-cells.

As before, these cells are able to mount an effective attack against the specific pathogen in the event of future infection. Memory cells remain in the lymphatic system where they can live for many years.

Other cells lose their co-stimulatory molecules and become effector cells, which migrate out into the surrounding tissue to participate in effector responses to eliminate infection. These cells die within a few weeks.

Both B-cell and T-cell clonal proliferation is driven by the presence of antigen. As soon as the antigen has been destroyed, the whole immune response switches off, leaving more cells in the system sharing the same specificity than existed prior to the original infection.