T helper cell
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A T helper cell (sometimes also known as effector T cells or TH cells) are a group of lymphocytes (a type of white blood cell or leukocyte) that play a cornerstone role in establishing and maximising the ability of the immune system. These cells are very unusual because they have no cytotoxic or phagocytic activity. This means they cannot kill infected cells or invading pathogens, and without other immune cells they would usually be considered useless against an infection.
TH cells are involved in activating and directing other immune cells, and are particularly important during the establishment of the acquired immune system. They are essential in determining B cell antibody class switching, in the activation and growth of killer T cells, and in maximising bactericidal activity of phagocytes such as macrophages. It is this diversity in function and its role in influencing other cells that give helper T cells their namesake.
Mature TH cells are believed to always express the surface protein CD4. T cells expressing CD4 are also known as called CD4+ T cells. It appears that CD4+ T cells almost always have a pre-defined role as helper T cells within the immune system. The importance of CD4+ T cells can be seen via HIV infection, where the virus infects cells that are CD4+ (including T cells). Towards the end of a HIV infection, there is decrease in functional CD4+ T cells, resulting in symptoms known as AIDS. There are rare disorders, probably genetic in etiology, that result in dysfunctional CD4+ T cells that result in similar symptoms; many of which are fatal (see [[CD4+ lymphocytopenia]]).
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Activation of naïve helper T cells
Following T cell development, matured naïve (meaning they have never been exposed to the antigen they are specific for) T cells leave the thymus and begin to spread throughout the body, including in the lymph nodes. Like all T cells, they express T antigen receptors (also known as the T cell receptor or TcR) that has an affinity with Class II MHC molecules. This affinity is believed to be determined via CD4 during maturation in the thymus. Class II MHC proteins are only found on the surface of professional antigen-presenting cells (APCs). Professional antigen presenting cells are primarily dendritic cells, macrophages and B cells. The antigens that bind to MHC proteins are almost always peptides.
Primary antigen exposure
Following an infection, professional antigen-presenting cells with processed antigen travel from the site of infection to the lymph nodes and begin to present various antigen peptides that bind to either MHC Class I and Class II. Some APCs also express native (or unprocessed) antigen, such as follicular dendritic cells, but unprocessed antigens do not interact with T cells and have no role in their activation. T cells dwelling within the lymph nodes are exposed to APCs and those that are capable of binding with antigen-bound MHC begin to activate. Memory T cells are also re-activated this way (excluding the verification step) if the body is again exposed to the same antigen.
CD4 is believed to be important for TH cell stabilisation during activation, possibly by binding to specific portions of the Class II MHC molecule. Further stabilisation occurs between the adhesion molecules ICAM on the APC, and LFA-1 on the T cell. These molecules stick together and stabilise the binding between the two cells, giving the cells enough time to interact and activate. CD45 (or common leukocyte antigen) is also required for T cell activation, but the actual role of the extracellular portion of CD45 is unknown. The extracellular region has many isoforms, and is believed to change depending on the cell's status. In T cells, CD45 shortens in length following activation (CD45RA+ to CD45RO+), and therefore it has been proposed that CD45 may affect T cell accessability to other cells and thus increases the affinity level required for initial activation.
Verification
Once the naïve T cell has been exposed to a presented antigen the T cell requires the activation of a second independent biochemical pathway. If the second signal is not present during initial exposure, the T cell become anergic; the cell will not respond to antigen in any future interaction even if both signals are present.
This second signal involves the interaction between CD28 on the CD4+ T cell with the protein CD80 (B7.1) or CD86 (B7.2) that is expressed on professional APC's. Both CD80 and CD86 activate CD28. These proteins are known as co-stimulatory molecules, and they are used as a confirmation mechanism within the T cell to ensure that the source of the antigen is foreign (since only APC's express them). This helps ensure that the T cell will only activate against antigens that are not from the host. This is an adjunct to the self/non-self recognition that has already been "learned" by the T cell in the thymus during development. This step is especially critical in inhibiting the activation of self-recognising cytotoxic T cells that had not been eliminated in the thymus. Once the T cell has successfully been activated, this second mechanism is no longer necessary; signalling from the TcR pathways will suffice.
Proliferation
If both stimulatory signals occur, the CD4+ T cell makes itself proliferate. It does this by producing a potent T cell growth factor called interleukin-2 (IL-2). It also will being to produce all of the sub-units of the IL-2 receptor (IL-2R). The released IL-2 binds to its receptor on the same (or other) activated T cell, resulting in auto-regulation (also known as autocrine stimulation). After many cell generations, the progenitors differentiate into effector TH cells, memory TH cells, and suppressor TH cells.
- Effector TH cells secrete cytokines, proteins or peptides that stimulate or interact with other leukocytes, including TH cells.
- Memory TH cells retain the TcR affinity of the originally activated T cell, and will be called upon to act as effector cells if they are needed during a secondary immune response.
- Suppressor TH cells do not activate or promote immune function following proliferation, but decreases it instead. It is believed that self-limitation is essential for the prevention of various auto-immune diseases.
Determination of the effector T cell response
Helper T cells are capable of influencing the actions of a variety of immune cells, and the response generated (including the extracellular signals such as cytokines) can be essential for a successful outcome from infection. In order to be effective they must determine which cytokines will be the most useful or beneficial in the current challenge to the immune system.
TH1/TH2 Model for helper T cells
Proliferating helper T cells that develop into effector T cells differentiate into two major subtypes of cells known as TH1 and TH2 cells (also known as Type 1 and Type 2 helper T cells respectively). These subtypes are defined on the basis of the specific cytokines they produce. TH1 cells produce interferon-gamma (or IFN-gamma) and lymphotoxin (also known as tumor necrosis factor-beta or TNF-beta), while TH2 cells produce interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-13 (IL-13), among numerous other cytokines. The TH1/TH2 model also states that interleukin-12 (IL-12) plays an essential role during TH1 development, but IL-12 is not produced by helper T cells, but by certain professional APCs, such as activated macrophages and dendritic cells. Interleukin-2 is associated with TH1 cells, and its production by helper T cells is necessary for the proliferation of cytotoxic CD8+ T cells, but this association with TH1 may be misleading; IL-2 is produced by all helper T cells early in their activation.
Given the relative specificity of the cytokines released by either response on particular sections of the immune system it has been suggested that both TH groups play separate roles during an immune response. That is; TH1 cells are necessary in maximising the killing efficacy of the macrophages and in the proliferation of cytotoxic CD8+ T cells, therefore their primary role during an immune response is to activate and proliferate these cells. TH2 cells express many cytokines, many of which are essential in stimulating B-cells with antibody class switching and increased antibody production; TH2 cells are therefore considered necessary for the full maturation of the humoral immune system.
This primary association between the cytokines of T</sub>H</sub> responses and the cells mentioned in the previous paragraph does not define all of the effects activated helper T cells can have on the immune system. Some cytokines also act on helper T cells themselves (or on other immune cells, such as interleukin-5 upon eosinophils). Some of the cytokines in both groups play an important role in the preservation of the TH response; which is generally believed to have been primarily determined during the initial activation of the T cell.
The Type 2 response not only promotes its own response via the action of interleukin-4 on helper T cells (which promotes the expression of TH2 cytokines including itself), but also expresses interleukin-10 (IL-10), a cytokine that inhibits a variety of cytokines including interleukin-2 and interferon-gamma in helper T cells, and IL-12 in dendritic cells and macrophages. The TH2 response promotes both the production of its own cytokines while inhibiting the establishment of the TH1 response.
There is a similar phenomenon with the Type 1 response. The Type 1 cytokine interferon-gamma increases the production of interleukin-12 by dendritic cells and macrophages, and via positive feedback by IL-12, promotes the TH1 response. IFN-gamma also inhibits the production of cytokines such as interleukin-4, an important cytokine associated the Type 2 response, and thus it also acts to preserve its own response.
Complexities surpassing the TH model
The interactions between cytokines from the TH1/TH2 model can be more complicated in some animals. For example, the TH2 cytokine IL-10 inhibits the cytokine production of both TH subsets in humans. As human IL-10 (coded hIL-10) suppresses T cell proliferation and cytokine production but ensures that plasma cells continue to produce high levels of antibodies, it has been proposed that hIL-10 protects the immune system from the over-stimulation of helper T cells while still maximising antibody production.
There are also other T cells that can also influence the expression and activation of helper T cells, such as natural suppressor T cells, as well as the TH3 subset of helper T cells. Terms such as "regulatory" and "suppression" have become ambiguous after the discovery that helper CD4+ T cells are also capable of regulating their own response outside of dedicated suppressor cells.
The major difference in "suppressor" (or "natural regulatory") T cells is that they are always immuno-suppressive, while effector T cell groups usually begin with immune-promoting cytokines and then may release inhibitory cytokines later in its repertoire. The latter is a feature of TH3 cells, which transform into a suppressor subset after its initial activation and cytokine production.
Both suppressor T cells and TH3 cells produce the cytokine transforming growth factor-beta (TGF-beta) and IL-10. Both cytokines are inhibitory to helper T cells, TGF-beta being inhibitory to the majority of immune cells.
Considering many of the cytokines discussed above are also expressed by other immune cells (see individual cytokines for details) it is obvious that while the original TH1/TH2 model is enlightening and potentially gives insight into the functions helper T cells have, it is far too simple to define the entire role of helper T cells throughout a response.
Role of helper T cells in disease
Considering the diverse and important role helper T cells play in the immune system, it is not suprising that these cells often play an important role in many diseases. They also appear to make mistakes, or at least generate responses that can be non-benificial to destructive on the host.
Helper T cells and Hypersensitivity
The immune system must achieve a balance of sensitivity in order to respond to foreign, but not host, antigens. When the immune system responds to very low levels of antigen that it usually shouldn't respond to, a hypersensitivity response occurs. Hypersensitivity is the cause of allergy and some auto-immune disease.
Hypersensitivity can be divided into four types:
Type 1 hypersensitivity includes common immune disorders such as asthma, allergic rhinitis (hay fever), eczema (hives), and anaphylaxis. These reactions all involve IgE antibodies, which require a TH2 response during their development. Preventative treatments, such as corticosteroids, focus on suppression of mast cells or other allergic cells; T cells do not play a primary role during the actual inflamatory response. It's important to note that the related "type" of hypersensitivity does not correlate to the "response" in the TH model.
Type 2 and Type 3 hypersensitivity both involve complications from the function of poor antibodies. In both of these reactions, T cells may play an accomplice role in generating these auto-specifc antibodies, although some of these reactions under Type 2 hypersensitivity would be considered normal in a healthy immune system. The understanding of the role of helper T cells in these responses is limited and it is generally thought that TH2 cytokines would promote such a disorder. For example, studies have suggested that lupus (and other auto-immune diseases of similar nature) can be linked to the production of TH2 cytokines.
Type 4 hypersensitivity, also known as delayed type hypersensitivity, are caused via the over-stimulation of immune cells, commonly lymphocytes and macrophages, resulting in chronic inflammation and cytokine release. Antibodies do not play a direct role in this allergy type. T cells play an important role in this hypersensitivity, as they both activate against the stimulus itself, and promote the activation of other cells; particularly macrophages, via TH1 cytokines.
Other cellular hypersensitivities include killer T cell mediated auto-immune disease, and a similar phenomenon; rejection of transplant organs. During the formation of these disease states, the helper T cells play an essential role. In order to create sufficient auto-reactive killer T cells, interleukin-2 is required, and this is produced by CD4+ T cells. CD4+ T cells can also stimulate cells such as natural killer cells and macrophages via cytokines such as IFN-gamma, encouraging cytotoxic cells to kill host cells. It is important to note that the same mechanisms that cause killer T cell auto-immunity mimics the response against viruses. The difference in T cell mediated auto-immune disease is that the antigen recognition system fails, and thus the immune system mistakenly believes that a self-antigen is foreign, and thus attacks it.
It should be noted that some of this is a simplification, and that many auto-immune diseases are more complex; such as rheumatoid arthritis, where both antibodies and immune cells play a role in the pathology. Generally the immunology of most auto-immune diseases is not well understood.
HIV infection
Perhaps the best example of the importance of CD4+ T cells is demonstrated with human immunodeficiency virus (HIV) infection. HIV infects cells that present CD4 on their surface, and therefore also infects macrophages and dendritic cells (since they express CD4 at a low levels) as well as some T cells. It is believed that during the non-symptomatic phase of the infection HIV has relatively low affinity towards T cells, thus any decrease in CD4+ T cells is compensated for with the production of new cells. Once the virus becomes lymphotropic (or T-tropic) however, it begins to infect CD4+ T cells much more efficiently (likely due to a change in the co-receptors it binds to during infection).
At this point, CD4+ T cells are destroyed more quickly than they can be replaced by the bone marrow, and thus functional CD4+ T cell levels decrease to below the critical level required for full antigen cover. The lack of full antigen recognition generates the core symptoms of acquired immunodeficiency syndrome (AIDS). Once this has occurred, various antigens, and later entire pathogens, begin to break through T cell recognition and thus do not develop a helper T cell response. This allows for opportunistic infections that require a strong helper T cell response for successful removal. Two components of the immune system are particularly affected in AIDS, due to its CD4+ T cell dependency:
- CD8+ T cells are not stimulated sufficiently during virus infections, making AIDS patients very susceptible to a huge variety of viruses, including itself. This decline in killing of CD4+ T cells results in the virus surviving for longer, increasing proliferation of the virus and accelerating the disease.
- Antibody class switching decreases significantly once helper T cell function fails. The immune system loses the ability to improve the specificity of their antibodies, while a strong decline occurs in the production of very important antibody groups such as IgG and IgA. All of this results in an increased susceptibility to aggressive bacterial infections, especially in areas of the body not accessible by IgM antibodies.
If the patient does not respond to HIV treatment they will succumb usually to either cancers or infections, because the immune system finally reaches a point where it is no longer coordinated or stimulated enough to deal with disease.
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