T helper cell
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T helper cells (also known as effector T cells or Th cells) are a sub-group of lymphocytes (a type of white blood cell or leukocyte) that play an important role in establishing and maximising the capabilities of the immune system. These cells are unusual in that they have no cytotoxic or phagocytic activity; they cannot kill infected host (also known as somatic) cells or 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 in the immune system. They are essential in determining B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximising bactericidal activity of phagocytes such as macrophages. It is this diversity in function and their role in influencing other cells that gives T helper cells their name.
Mature Th cells are believed to always express the surface protein CD4. T cells expressing CD4 are also known as CD4+ T cells. CD4+ T cells are generally treated as having a pre-defined role as helper T cells within the immune system, although there are known rare exceptions. For example, there are sub-groups of suppressor T cells, natural killer T cells, and cytotoxic T cells that are known to express CD4 (although cytotoxic examples have been observed in extremely low numbers in specific disease states, they are usually considered non-existent). All of the latter CD4+ T cell groups are not considered T helper cells, and are beyond the scope of this article.
The importance of helper T cells can be seen from HIV, a virus that infects cells that are CD4+ (including helper T cells). Towards the end of an HIV infection the number of functional CD4+ T cells falls, which leads to the symptomatic stage of infection known as the acquired immune deficiency syndrome (AIDS). There are rare disorders, probably genetic in etiology, that result in the absence or dysfunction of CD4+ T cells. These disorders produce similar symptoms, and many of these are fatal (see CD4+ lymphocytopenia).
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[edit] Activation of naïve helper T cells
Following T cell development, matured naïve (meaning they have never been exposed to the antigen they can respond to) T cells leave the thymus and begin to spread throughout the body, including the lymph nodes. Like all T cells, they express the T cell receptor/CD3 complex. The T cell receptor (TcR) consists of both constant and variable regions, the latter of which determines what antigen the T cell can respond to. CD4+ T cells have TcRs with an affinity for Class II MHC, and it is believed that CD4 is involved in determining MHC affinity during maturation in the thymus. Class II MHC proteins are generally only found on the surface of professional antigen-presenting cells (APCs). Professional antigen presenting cells are primarily dendritic cells, macrophages and B cells, although dendritic cells are the only cell group that expresses MHC Class II constitutively (at all times). Some APCs also bind native (or unprocessed) antigens to their surface, such as follicular dendritic cells, but unprocessed antigens do not interact with T cells and are not involved in their activation. The antigens that bind to MHC proteins are always short peptides, 8-10 amino acids long for MHC Class I, and up to 25 or so for MHC Class II.
[edit] Initial antigen exposure (Signal 1)
During an immune response, professional APCs endocytose (absorb) foreign material (typically bacteria or viruses), and undergo antigen processing, travelling from the site of infection to the lymph nodes. Once at the lymph nodes, the APC begins to present antigen peptides that are bound to Class II MHC, allowing CD4+ T cells that express high-affinity TcR's against the peptide/MHC complex to activate.
When a Th cell encounters an APC, the TcR-CD3 complex binds to the peptide-MHC complex present on the surface of professional APC's. CD4, a co-receptor of the TCR complex, then binds to another section of the MHC molecule. These interactions increase the accessability of the intracellular kinases within the TcR, CD3 and CD4 proteins, and via phosphorylation they activate each other. With the assistance of another kinase present within the intracellular section of CD45 (common leukocyte antigen), these kinases stimulate major biochemical pathways in the cytosol of the Th cell. These active pathways are known as Signal 1 of T cell activation, as it is the primary activating signal of the Th cell. Upon subsequent encounters with a given antigen, memory T cells are re-activated via the same TCR pathway.
The binding of the antigen-MHC to the TCR complex and CD4 may also help the APC and the Th cell adhere during Th cell activation. However, the protein LFA-1 on the T cell and the ICAM on the APC are the primary molecules in cell adhesion.
It is unknown what role the relatively bulky extracellular region of CD45 plays during cell interactions, but it is known that CD45 has various isoforms that change in size depending on the Th cell's activation and maturation status. For example, CD45 shortens in length following Th activation (CD45RA+ to CD45RO+), but whether this change in length influences activation is unknown. It has been proposed that the larger CD45RA+ may affect the decrease the accessibility of the T cell receptor for the antigen-MHC molecule, thereby forcing an increase in the affinity (and specificity) of the T cell required for activation. Once the activation has occurred however, CD45 shortens, allowing easier interactions and activation as an effector T helper cell.
[edit] Verification (Signal 2)
Once the naïve T cell has received the first TcR/CD3 signal, a second independent biochemical pathway, known as Signal 2, must also be activated. This verification step allows T cells to confirm that they are responding to a foreign antigen, reducing the risk of T cell autoimmunity. If this second signal is not present during initial antigen exposure, the T cell presumes that it is not responding to a foreign protein. It treats itself as being auto-reactive, and results in the cell becoming anergic (anergy is developed from the biochemical changes Signal 1 have without the protection of Signal 2). Anergic cells will not respond to any antigen in the future, even if both signals are present later on. These cells are generally believed to circulate with no value until they are recycled at the end of their life-span.
The second signal involves an interaction between CD28 on the CD4+ T cell and the proteins CD80 (B7.1) or CD86 (B7.2) on the professional APCs. Both CD80 and CD86 activate the CD28 receptor. These proteins are known as co-stimulatory molecules, and it is believed to act as a quality control to ensure that the antigen recognised is foreign.
Although this stage is necessary for the activation of naïve helper T cells, its importance is best demonstrated during the similar activation mechanism of CD8+ cytotoxic T cells. CD8+ T cells have no true bias towards foreign sources, since most somatic cells express MHC Class I. Using Signal 2, CD8+ T cells can use the activation of CD28 to confirm that they are interacting with a foreign antigen (as it must come from a professional APC), and that they should become reactive.
Once the naïve T cell has both pathways activated, there are permanent biochemical changes to the T cell. The second signal is then obsolete; the first signal from the TcR pathways suffices in later interactions. This is also true for memory T cells, allowing for relatively rapid responses during reinfection because the extra stages for primary activation are unnecessary.
[edit] Proliferation
If both stimulatory signals are active within the helper T cell, the cell then allows itself to proliferate. It does this by producing a potent T cell growth factor called interleukin-2 (IL-2). The activated T cell will also begin to produce all of the sub-units of the IL-2 receptor (CD25 or IL-2R). The IL-2 that is produced is released from the cell, and then binds to IL-2 receptors on the same (or other) activated T cells, a process known as auto-regulation (or 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 themselves.
- Memory Th cells retain the antigen affinity of the originally activated T cell, and are used to act as later effector cells during a second immune response (e.g. if there is re-infection of the host at a later stage).
- Suppressor T cells do not promote immune function, but act to decrease it instead. Despite their low numbers during an infection, these cells are believed to play an important role in the self-limitation of the immune system; they prevent the development of various auto-immune diseases.
The production of IL-2 by helper T cells is also necessary for the proliferation of activated CD8+ T cells. Without helper T cell interactions, CD8+ T cells do not proliferate and eventually become anergic. This cross-reliance on helper T cells is another way the immune system tries to prevent T cell-mediated auto-immune disease.
[edit] Determination of the effector T cell response
Helper T cells are capable of influencing a variety of immune cells, and the T cell response generated (including the extracellular signals such as cytokines) can be essential for a successful outcome from infection. In order to be effective, helper T cells must determine which cytokines will allow the immune system to be most useful or beneficial for the host. Understanding exactly how helper T cells respond to immune challenges is currently of major interest in immunology, because such knowledge may be very useful in the treatment of disease and in increasing the effectiveness of vaccination.
[edit] 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 (IFN-γ) and tumor necrosis factor-beta (TNF-β, also known as lymphotoxin), 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, however IL-12 is not produced by helper T cells themselves, but by certain professional antigen presenting cells, such as activated macrophages and dendritic cells. Interleukin-2 was classically associated with Th1 cells, but this association may be misleading; IL-2 is produced by all helper T cells early in their activation.
Both of these cytokine profiles appear to be biased in the type of immune stimulation they promote. For example, cytokines in the Th1 response maximises the killing efficacy of the macrophages and in the proliferation of cytotoxic CD8+ T cells, and it has been suggested that their primary role during an immune response is to activate and/or proliferate the cellular immune system. Th2 cells express a variety of cytokines, many of which stimulate B-cells into proliferation, to induce B-cell antibody class switching, and to increase antibody production. Th2 cells are therefore considered necessary for the full maturation of the humoral immune system.
The stimulation of the above systems is only one way helper T cells manipulate the immune system. Many of the cytokines also act on helper T cells themselves, or on other immune cells, such as the actions of interleukin-5 on eosinophils. There are cytokines in both Th responses that play an important role in preserving the response itself, or in suppressing other functions of the immune system.
The Type 2 response promotes its own profile using two different cytokines. Interleukin-4 acts on helper T cells to promote the production of Th2 cytokines (including itself; it is auto-regulatory), while interleukin-10 (IL-10) inhibits a variety of cytokines including interleukin-2 and interferon-gamma in helper T cells and IL-12 in dendritic cells and macrophages. The combined action of these two cytokines suggests that once the T cell has decided to produce these cytokines, that decision is preserved (and also encourages other T cells to do the same).
A similar phenomenon occurs 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, IL-12 stimulates the production of IFN-gamma in helper T cells, thereby promoting the Th1 profile. 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.
While we know about the types of cytokine patterns helper T cells tend to produce, we understand less about how the patterns themselves are decided. Various evidence suggests that the type of APC presenting the antigen to the T cell has a major influence on its profile. Other evidence suggests that the concentration of antigen presented to the T cell during primary activation influences its choice. The presence of some cytokines (such as the ones mentioned above) will also influence the response that will eventually be generated, but our understanding is nowhere near complete.
[edit] 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 cytokine production of both Th subsets in humans. Human IL-10 (coded hIL-10) suppresses the proliferation and cytokine production of all T cells and the activity of macrophages, but continues to stimulate plasma cells, ensuring that antibody production still occurs. As such, hIL-10 is not believed to truly promote the Th2 response in humans, but acts to prevent over-stimulation of helper T cells while still maximising the production of antibodies.
There are also other types of T cells that can also influence the expression and activation of helper T cells, such as natural suppressor T cells, along with less common cytokine profiles such 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 (and suppressing) their own responses outside of dedicated suppressor T cells.
One major difference with "suppressor" (or "natural regulatory") T cells is that they always suppress the immune system, while effector T cell groups usually begin with immune-promoting cytokines and then switch to 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-β) and IL-10. Both cytokines are inhibitory to helper T cells; TGF-beta suppresses the activity of most of the immune system.
Many of the cytokines in this article are also expressed by other immune cells (see individual cytokines for details), and it is becoming clear that while the original Th1/Th2 model is enlightening and gives insight into the functions of helper T cells, it is far too simple to define its entire role or actions. Some immunologists question the model completely, as some in vivo studies suggest that individual helper T cells usually do not match the specific cytokine profiles of the Th model, and many cells express cytokines from both profiles. That said, the Th model has still played an important part in developing our understanding of the roles and behaviour of helper T cells and the cytokines they produce during an immune response.
[edit] Role of helper T cells in disease
Considering the diverse and important role helper T cells play in the immune system, it is not surprising that these cells often influence the immune response against disease. They also appear to make occasional mistakes, or generate responses that would be politely considered non-beneficial. In the worst case scenario, the helper T cell response could lead to a disaster and the fatality of the host. Fortunately this is a very rare occurrence.
[edit] Helper T cells and Hypersensitivity
The immune system must achieve a balance of sensitivity in order to respond to foreign antigens without responding to the antigens of the host itself. When the immune system responds to very low levels of antigen that it usually shouldn't respond to, a hypersensitivity response occurs. Hypersensitivity is believed to be the cause of allergy and some auto-immune disease.
Hypersensitivity reactions can be divided into four types:
Type 1 hypersensitivity includes common immune disorders such as asthma, allergic rhinitis (hay fever), eczema, urticaria (hives) and anaphylaxis. These reactions all involve IgE antibodies, which require a Th2 response during helper T cell development. Preventative treatments, such as corticosteroids and montelukast, focus on suppressing mast cells or other allergic cells; T cells do not play a primary role during the actual inflammatory response. It's important to note that the numeral allocation of hypersensitivity "types" does not correlate (and is completely unrelated) to the "response" in the Th model.
Type 2 and Type 3 hypersensitivity both involve complications from auto-immune or low affinity antibodies. In both of these reactions, T cells may play an accomplice role in generating these auto-specific antibodies, although some of these reactions under Type 2 hypersensitivity would be considered normal in a healthy immune system (for example, Rhesus factor reactions during child-birth is a normal immune response against child antigens). The understanding of the role of helper T cells in these responses is limited but it is generally thought that Th2 cytokines would promote such disorders. For example, studies have suggested that lupus (SLE) 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 activate against the stimulus itself and promote the activation of other cells; particularly macrophages via Th1 cytokines.
Other cellular hypersensitivities include cytotoxic T cell mediated auto-immune disease, and a similar phenomenon; transplant rejection. Helper T cells are required to fuel the development of these diseases. In order to create sufficient auto-reactive killer T cells, interleukin-2 must be produced, and this is supplied by CD4+ T cells. CD4+ T cells can also stimulate cells such as natural killer cells and macrophages via cytokines such as interferon-gamma, encouraging these cytotoxic cells to kill host cells in certain circumstances.
The mechanism that killer T cells use during auto-immunity is almost identical to their response against viruses, and some viruses have been accused of causing auto-immune diseases such as Type 1 Diabetes mellitus. Cellular auto-immune disease occurs because the host antigen recognition systems fail, and the immune system believes, by mistake, that a host antigen is foreign. As a result, the CD8+ T cells treat the host cell presenting that antigen as infected, and go on to destroy all host cells (or in the case of transplant rejection, transplant organ) that express that antigen.
It should be noted that some of this section is a simplification, and that many auto-immune diseases are more complex; a well known example is rheumatoid arthritis, where both antibodies and immune cells are known to play a role in the pathology. Generally the immunology of most auto-immune diseases is not well understood.
[edit] HIV infection
Perhaps the best example of the importance of CD4+ T cells is demonstrated with human immunodeficiency virus (HIV) infection. HIV targets cells that express CD4, and can infect macrophages, dendritic cells (both groups express CD4 at low levels) and CD4+ T cells.
It has been proposed that during the non-symptomatic phase of HIV infection, the virus has a relatively low affinity towards T cells (and has a higher affinity for macrophages), resulting in a slow kill rate of CD4+ T cells by the immune system. This can then be compensated for via the production of new helper T cells from the thymus (originally from the bone marrow). Once the virus becomes lymphotropic (or T-tropic) however, it begins to infect CD4+ T cells far more efficiently (likely due to a change in the co-receptors it binds to during infection), and the immune system is overwhelmed.
At this point, functional CD4+ T cell levels begin to decrease, eventually to a point where the CD4+ T cell population is too small to recognise the full range of antigens that could potentially be detected. The lack of full antigen cover results in the core symptoms of acquired immune deficiency syndrome (AIDS). AIDS causes various antigens (and later entire pathogens) to break through T cell recognition, allowing opportunistic infections that would normally elicit a helper T cell response to bypass the immune system. While these complete bypass situations only occur when the helper T cell response is absolutely necessary for infection clearance, most infections increase in severity and/or duration because the immune system's helper T cells provide a weaker contribution to a less efficient immune response.
Two components of the immune system are particularly affected in AIDS, due to its CD4+ T cell dependency:
- CD8+ T cells are not stimulated as effectively during the AIDS period of HIV infection, making AIDS patients very susceptible to most viruses, including HIV itself. This decline in killing of CD4+ T cells results in the virus being produced for a longer period (the infected CD4+ T cells are not killed as quickly), increasing the proliferation of the virus, and accelerating the development of the disease.
- Antibody class switching declines significantly once helper T cell function fails. The immune system loses the ability to improve the affinity of their antibodies, and are unable to generate effective amounts of important antibody groups such as IgG and IgA. These effects are primarily due to a lack of helper T cells that interact with the peptide fragments of B lymphocyte antigens. Another symptom of AIDS is the reduction of antibody levels due to a lower level of Th2 cytokines (and less interactions by helper T cells). All of these complications result 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 (or does not receive) HIV treatment they will succumb usually to either cancers or infections; the immune system finally reaches a point where it is no longer coordinated or stimulated enough to deal with the disease.
