T Lymphocytes



T lymphocytes are a major component of the acquired immune response and are essential for the co-ordination of the immune system as a whole. If the function of T cells is defective, the entire immune system may perform suboptimally.

Three types of T cells exist, helper T cells, cytoxic T cells and natural killer cells.

Helper T Cells

Helper T cells (Th) are the leaders of the immune system. To push an already overstretched military analogy even further, they are the generals that organise the rest of the troops but do not fight directly; helper T cells do not kill other cells or micro-organisms.

If a helper T cell encounters its target antigen, binding of the antigen to the T cell receptor will active the helper T cell. Once stimulated, this activated helper T cell assists in the activation of cytotoxic T cells, enables B cells to switch their immunoglobulin subtype (including from IgM to IgG), as well as inducing the B cells to undergo hypermutation of the antigen binding site of their immunoglobulin. Helper T cells also secrete a variety of cytokines that direct the action of other components of the immune system.

Activated helper T cells can specialise along two different lines (additional lines have more recently been described).

Type one helper T cells focus on facilitating and optimising the antibody response and are therefore particularly useful against bacteria, as well as viruses when the viruses are in the extracellular environment.

Type two helpter T cells deal more with the cell mediated / cytotoxic response and are therefore important in the eradication of parasites and intracellular infections such as viruses.

A third population of helper T cells exist, memory T cells, which are largely dormant and act as a reserve that can generate a population of effector T helper cells if required.

Helper T cells do not recognise raw antigen. Instead, the antigen has first to be processed by an antigen presenting cell , then displayed on the surface of the antigen presenting cell complexed with a class two MHC molecule. Helper T cells then recognise this processed, MHC class two bound antigen. Interposing the antigen presenting cell between the T cell and the foreign antigen acts as form of regulation for T cell activation. An inappropriate T cell response can wreak havoc and in effect the antigen presenting cell may be considered to be acting as a form of filter that ensures that the T cells are only exposed to external antigens rather than host antigens.

Regulator T cells may be considered as a form of helper T cell, on the basis that they are CD4 positive cells, although it could be argued that they might merit their own separate category. Regulator T cells help to calm down the T cell response once an infection has been eliminated. They also suppress any T cells that react against host antigens.

Cytotoxic T Cells

Cytotoxic T cells kill other cells, usually host cells that have been infected by a micro-organism and have presented processed antigen from that micro-organism on their surface membrane in a bound complex with an MHC class one molecule. The T cell receptor of the cytotoxic T cell allows the T cell to identify the infected cell. The cytotoxic T cell kills the infected cell by inducing apoptosis through the Fas pathway and also in a more aggressive fashion through the use of perforin. Perforin punches a hole in the membrane of the infected cell. This in itself is damaging to the osmotic integrity of the cell but the T cell then follows up by injecting granzyme B into the infected cell; granzyme B also initiates apoptosis.

Aberrant activity of the cytotoxic T cell system can cause significant damage to host tissues, so the initial activation of cytotoxic T cells is stringent. Once a young cytotoxic T cell has graduated from its basic training in the thymus its killing mechanisms are non-functional. If the immune system encounters the cytotoxic T cell's cognate antigen, this antigen has first to be processed by an antigen presenting cell and recognised by a helper T cell. The helper T cell then instructs the antigen presenting cell to upregulate its MHC class one molecules, allowing the antigen presenting cell to display the antigen to the young cytotoxic T cell. Even then, the young cytotoxic T cell will become only activated if it receives co-stimulation in the form of interleukin-2 that is secreted by the helper T cell.

Once the cytotoxic T cell has been inducted in this fashion, reactivation in the future requires only exposure to the target antigen on any MHC class one expressing cell, combined with a lower degree of stimulation from helper T cells.

Natural Killer Cells

Natural killer cells are a specialised form of T lymphocyte that are sometimes referred to as large granular lymphocytes. They do not possess the T cell receptor and lack other T cell related antigens. Furthermore, they contain toxic granules that are similar to those used by macrophages and neutrophils and can kill cells by discharging the contents of these granules. In common with cytotoxic T cells they can also deploy the Fas method of inducing apoptosis, as well as wielding perforin and granyzme B.

As is sometimes the case with medical terminology, the first name that seems good for a new type of cell or molecule later transpires to be not so appropriate or even to be misleading. Natural killer cells were so dubbed because it was believed that they needed little stimulus to be activated and as such were prone to kill anything that moved and looked a bit dodgy. However, it has emerged that the activation of natural killer cells and the triggering of their cytotoxic behaviour is more strictly controlled.

Natural killer cells will attack cells that have a reduced number of MHC molecules on their surface. This is an adaptation to the strategy of some intracellular organisms that try to evade the immune system by preventing the infected cell from displaying antigen on its surface. It is suggested that this aspect of natural killer cell behaviour reflects an inhibitory effect of MHC class one molecules on them; if inadequate MHC class one inhibition is received, the natural killer cell activates.

Natural killer cells possess a receptor for the Fc portion of the immunoglobulin molecule. If this receptor attaches to an antibody that is bound to a pathogen, the natural killer cell is directed against this pathogen.

Activation of natural killer cells can also be achieved by certain cytokines. Interleukin-2 secreted by helper T cells activates natural killer cells while interferon secreted by macrophages induces the natural killer cell to express interleukin-2 receptors.

The T cell Receptor

The T cell receptor (TCR) enables the helper T cells and cytotoxic T cells to recognise their target antigen. In B cells, this role is discharged by IgD or IgM that is anchored in the cell membrane and appropriately coupled to the relevant signal transduction proteins. Thus, the B cell's effector agent (antibody) also serves as the detector for the target. However, in T cells the effector apparatus is distinct from the detector.

The T cell receptor is complexed with the CD3 molecule. The CD3 molecule is a signal transduction protein that relays binding of the antigen to the nucleus of the T cell. The TCR-CD3 complex is itself combined with either CD4 or CD8 and only with this whole unit can the T cell recognise processed antigen that is presented attached to an MHC molecule. Helper T cells use CD4 and cytotoxic T cells employ CD8.

The TCR has two subunits. In 95% of cases these are of the alpha and beta subtype. However, 5% of T cells possess gamma-delta subunits. These T cells operate in mucosal surfaces and do not require interaction of their receptor with MHC molecules for it to function.

T Cell Development

The stem cells which give rise to T cells (as well as B cells) are located in the bone marrow. The very early T cell precursors to which these stem cells give rise migrate to the thymus. The thymus is a bilobed organ located in the anterior mediastinum. It is large in the fetus but undergoes considerable atrophy by adulthood to the extent that it is often not identified during a post mortem examination of an adult.

The young T cells begin the first step of their education and training in the cortex of the thymus. At this stage the T cells express CD4 and CD8. In the cortex they are tested to determine if they can recognise class one and class two MHC molecules. If a T cell cannot do this, it dies.

Once the young T cell has passed the test in the cortex, it selects either CD4 or CD8 to be part of the complex with its T cell receptor and thus commits to being either a helper T cell (CD4) or cytotoxic T cell (CD8). The T cell then enters the medulla. In the medulla it encounters antigen presenting cells. T cells which bind strongly to the medullary antigen presenting cells die: strong binding at this stage in the maturation of the T cell means that the cell either identifies the MHC molecule alone as a target antigen (which would cause the T cell to be directed against host cells) or is directed against a host antigen (with the result that the T cell would initiate a response against all the cells that express this host antigen). The environment of the thymic medulla is configured to ensure it expresses numerous host antigens from non-thymic tissues and thus maximises the exposure of the young T lymphocytse to host antigens.

The T cells that negotiate the screening step in the thymic medulla are released into the peripheral blood and circulate to lymphoid organs (lymph nodes, spleen, mucosal associated lymphoid tissue and the tonsils) to await exposure to their target antigen.

The vast majority of T cells are created and educated in utero and during childhood. The generation of completely new cells (as opposed to replenishing numbers by the proliferation of memory cells) is much lower in adulthood and therefore the thymus atrophies.