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 acquired 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 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. 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). These latter CD4+ T cell groups would not be considered T helper cells, and are beyond the scope of this article.
The importance of CD4+ T cells can be seen via HIV infection, a virus that infects cells that are CD4+ (including helper 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 producing similar symptoms; many of which are fatal (see CD4+ lymphocytopenia).
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 in the lymph nodes. Like all T cells, they express the CD3/T cell receptor (or TcR) complex. The T cell receptor determines what antigen the T cell can respond to, and interacts with major histocompatibility complex (MHC) molecules. In the case of CD4+ T cells, the TcR has an affinity with Class II MHC, and it is believed that CD4 is involved in determining this 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 endogenously (that is, at all times). The antigens that bind to MHC proteins are always peptides.
Primary antigen exposure
During an infection, professional antigen-presenting cells process antigen, travel from the site of infection to the lymph nodes and begin to present different antigen peptides that are bound to either Class I or Class II MHC. Some APCs also express native (or unprocessed) antigen, such as follicular dendritic cells, but unprocessed antigens do not interact with T cells and are not involved in their activation. T cells within the lymph node are exposed to these APCs and those that are capable of strongly interacting with the antigen-bound MHC begin to activate. Memory T cells are also re-activated this way (excluding the next 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 cells via adhesion molecules that are on the cell surface. For example, LFA-1 on the T cell binds onto ICAM on the APC. These adhesion molecules make the cells sticky and thereby stabilises the cells long enough to interact and activate. CD45 (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 of CD45 has many isoforms, and is believed to change depending on the cell's activation and maturation status. In T cells, CD45 shortens in length following activation (CD45RA+ to CD45RO+), and so it has been proposed that CD45 may affect the accessibility of the T cell receptor with MHC Class II, thereby increasing the affinity (and specificity) of the T cell necessary for activation.
Verification
Once the naïve T cell has interacted with a MHC presented antigen, the T cell requires the activation of a second independent biochemical pathway. If the second signal is not present during initial exposure of antigen, the T cell become anergic. Anergic cells will not respond to any antigen in the future, even if both signals are present later on.
This second signal involves the interaction between CD28 on the CD4+ T cell with the protein CD80 (B7.1) or CD86 (B7.2) on the professional APC's. Both CD80 and CD86 activate CD28. These proteins are known as co-stimulatory molecules, and it has been proposed that they act as a quality control system within the T cell, ensuring that the antigen is foreign. It is considered to be another mechanism to protect the host against T cell auto-immunity (as an adjunct to the negative selection stage of self/non-self recognition "learned" by the T cell during development).
Although this stage is necessary and important for the activation of naïve helper T cells, its importance is best demonstrated during the similar activation of CD8+ cytotoxic T cells. The TcR/CD3/CD8 proteins on CD8+ T cells do not have any specific affinity towards professional APCs (as almost all cells express MHC Class I), and therefore without other interactions the cytotoxic T cells cannot determine if it is auto-reactive. Since CD80 and CD86 are only present on professional APC's, their interaction with CD28 confirms that the T cell is interacting with a foreign antigen (as it is coming from a professional APC).
The verification step reinforces that the helper T cell is targeting a foreign antigen, and in doing so reduces the risk of autoimmunity. Once the T cell has both pathways activated during its first exposure to antigen, the second signal is no longer necessary; the biochemical signalling from the TcR pathways will suffice in later interactions.
Proliferation
If both stimulatory signals are active within the helper T cell, the cell then makes itself proliferate. It does this by producing a potent T cell growth factor called interleukin-2 (IL-2). It also will begin to produce all of the sub-units of the IL-2 receptor (CD25 or 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 the Th cells themselves.
- Memory Th cells retain the TcR 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 activate or promote immune function, but act to decrease it instead. It is believed that despite their low numbers, these cells play an important role in the self-limitation of the immune system; preventing the development of various auto-immune diseases.
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 produced) can be essential for a successful outcome from infection. In order to be effective helper T cells must determine which cytokines will be the most useful or beneficial for the host. It must do so based on the type of challenge the immune system has. 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.
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-gamma) and tumor necrosis factor-beta (TNF-beta, 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 so it is believed that their primary role during an immune response is to activate and/or proliferate these cells. Th2 cells express a variety of cytokines, many of which stimulate B-cells into proliferation, to undergo 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 actions within the immune system.
The Type 2 response promotes itself using two different cytokines. Interleukin-4 acts on helper T cells to promote the production of Th2 cytokines (including itself), 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 amount of antigen that the T cell is exposed to 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.
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 protect the 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, and there are other 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 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-beta) 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.
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 considered, at best, to be 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.
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 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 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 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 but it is generally thought that Th2 cytokines would promote such a disorder. 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; the rejection of transplant organs. 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, thereby encouraging these cytotoxic cells to kill host cells in certain circumstances.
The same mechanisms that cause killer T cell auto-immunity is almost identical to the response against viruses, and some viruses have been accused of inducing auto-immune disease, 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 the host cell is virus infected. The CD8+ T cells then remember the host antigen as being foreign, and then go on to destroy all of the host cells (or the 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.
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 immunodeficiency syndrome (AIDS). AIDS allows various antigens (and later entire pathogens) to break through T cell recognition, resulting in no helper T cell response. This allows for various opportunistic infections that require a helper T cell response to bypass the immune system. 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 in AIDS, making AIDS patients very susceptible to most viruses, including HIV itself. This decline in killing of CD4+ T cells results in the HIV virus surviving for longer, increasing proliferation of the virus and accelerating the disease.
- Antibody class switching declines significantly once helper T cell function fails. The immune system loses the ability to improve the specificity of their antibodies, and the production of important antibody groups such as IgG and IgA decreases significantly due to a lack of cytokines such as IL-4. The production of all antibodies also declines because the Th2 cytokines that promote antibody production are no longer present in sufficient amounts. All of this results in an increased susceptibility to aggressive bacterial infections, especially in areas of the body not accessible by IgM antibodies.
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