T helper cell T helper cells (also known as Th cells) are a sub-group of lymphocytes, a type of white blood cell

, that play an important role in establishing and maximizing the capabilities of the immune system. These cells are unusual in that they have no cytotoxic or phagocytic activity; they cannot kill infected host cells (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 maximizing 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 and are referred to 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 regulatory 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. 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 immunodeficiency syndrome (AIDS). There are also some rare disorders that result in the absence or dysfunction of CD4+ T cells. These disorders produce similar symptoms, and many of these are fatal.

[edit]Activation of naïve helper T cells Following T cell development. also binds to a different section of the MHC molecule. professional antigen-presenting cells (APCs) endocytose (absorb) foreign material (typically bacteria or viruses). The antigens that bind to MHC proteins are always short peptides. which undergoes processing. on an APC. CD4. the APC begins to present antigen peptides that are bound to Class II MHC. and up to 25 or so for MHC Class II. such as follicular dendritic cells. 8-10 amino acids long for MHC Class I. [edit]Recognition (Signal 1) During an immune response. and it is believed that CD4 is involved in determining MHC affinity during maturation in the thymus. including the lymph nodes. a coreceptor of the TCR complex. allowing CD4+T cells that express the specific TCRs against the peptide/MHC complex to activate. the TCR-CD3 complex binds strongly to the peptide-MHC complex present on the surface of professional APC's. Once at the lymph nodes. The T cell receptor (TcR) consists of both constant and variable regions. When a Th cell encounters and recognises the antigen. although B cells are the only cell group that expresses MHC Class II constitutively (at all times). CD4+ T cells have TcRs with an affinity for Class II MHC. they express the T cell receptor-CD3 complex. the latter of which determines what antigen the T cell can respond to. These interactions bring these proteins closer . Specialised antigen presenting cells are primarily dendritic cells. naïve (meaning they have never been exposed to the antigen to which they can respond) T cells leave the thymus and begin to spread throughout the body. Class II MHC proteins are generally only found on the surface of specialised antigen-presenting cells (APCs). Some APCs also bind native (or unprocessed) antigens to their surface. but unprocessed antigens do not interact with T cells and are not involved in their activation. Like all T cells. matured. macrophages and B cells. then travels from the infection site to the lymph nodes.

thereby necessitating an increase in the affinity (and specificity) of the T cell for activation. These active pathways are known as Signal 1 of T cell activation. allowing the intracellular kinases present on the TCR. CD3 and CD4 proteins to activate each other via phosphorylation. these molecules activate the major biochemical pathways in the cytosol of the Th cell. 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. With the assistance of a phosphatase present on the intracellular section of CD45 (common leukocyte antigen). If this second signal is not present during initial antigen exposure. memory T cells are re-activated using the same TCR pathways. the T cell . [edit]Verification (Signal 2) Having received the first TcR/CD3 signal. Upon subsequent encounters with a given antigen. allowing easier interactions and activation as an effector T helper cell. known as Signal 2. but whether this change in length influences activation is unknown. It has been proposed that the larger CD45RA+ may decrease the accessibility of the T cell receptor for the antigen-MHC molecule. CD45 shortens. but the integrin protein LFA-1 on the T cell and ICAM on the APC are the primary molecules of adhesion in this cell interaction. but CD45 has various isoforms that change in size depending on the Thcell's activation and maturation status. as it is the first and primary pro-activation signal in a Th cell.together. This verification step is a protective measure to ensure that a T cell is responding to a foreign antigen. the naïve T cell must activate a second independent biochemical pathway. It is unknown what role the relatively bulky extracellular region of CD45 plays during cell interactions. For example. Once the activation has occurred however. CD45 shortens in length following Th activation (CD45RA+ to CD45RO+).

2) on the professional APCs. only the first signal is necessary for future activation. These cells are generally believed to circulate throughout the body with no value until they apoptose at the end of their lifespan. The second signal is then obsolete. This is also true for memory T cells. the biochemical changes induced by Signal 1 are altered. even if both signals are present later on.presumes that it is auto-reactive. Although the verification stage is necessary for the activation of naïve helper T cells. which is one example of learned immunity. This results in the cell becoming anergic (anergy is generated from the unprotected biochemical changes of Signal 1). These proteins are also known as co-stimulatory molecules. [edit]Proliferation Once the two signal activation is complete the T helper cell (Th) then allows itself to proliferate. It achieves this by releasing a potent T cell growth factor called interleukin 2(IL-2) which acts upon itself in an autocrine fashion. As naïve CD8+ T cells have no true bias towards foreign sources. The second signal involves an interaction between CD28 on the CD4+ T cell and the proteins CD80 (B7. Anergic cells will not respond to any antigen in the future. the importance of this stage is best demonstrated during the similar activation mechanism of CD8+ cytotoxic T cells. Once the naïve T cell has both pathways activated. Both CD80 and CD86 activate the CD28 receptor. these T cells must rely on the activation of CD28 for confirmation that they recognise a foreign antigen (as CD80/CD86 is only expressed by active APC's). Activated T cells also produce . allowing the cell to activate instead of anergise. Faster responses occur upon reinfection because memory T cells have already undergone confirmation and can produce effector cells much sooner. CD28 plays an important role in decreasing the risk of T cell auto-immunity against host antigens.1) or CD86 (B7.

The autocrine or paracrine secretion of IL-2 can bind that same Th cell or neighboring Th's via the IL-2R thus driving proliferation and clonal expansion. proteins or peptides that stimulate or interact with other leukocytes. enabling a fully functional receptor that can bind with IL-2. and are used to act as later effector cells during a second immune response (e. IL-4 and interferon gamma (IFN-γ). including Th cells.the alpha sub-unit of the IL-2 receptor (CD25 or IL-2R). Despite their low numbers during an infection. Regulatory T cells do not promote immune function.  Effector Th cells secrete cytokines. The Th cells receiving both signals of activation will then become Th0 cells (T helper 0) cell that secrete IL-2. if there is re-infection of the host at a later stage). [edit]Maturation After many cell generations. and regulatory Th cells. Memory Th cells retain the antigen affinity of the originally activated T cell. IFN-γ drives Th1 cell production while IL-10 and IL-4 inhibit Th1 cell production. IL-4 drives Th2 cell production and IFN-γ inhibits Th2 cells. Conversely.g. The Th0 cells will then differentiate into T h1 or T h2 cells depending on cytokine environment. but act to decrease it instead. memory Th cells. these cells are believed to play an important role in the self-limitation of the immune system. they have been shown to prevent the   . It should be noted that these cytokines are pleiotropic and carry out many other functions of the immune response. which in turn activates the T cell's proliferation pathways. the Th cell's progenitors differentiate into effector Th cells.

In order to be effective. . [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). CD8+ T cells do not develop effector function and eventually undergo apoptosis. Without helper T cell interactions. helper T cells must determine which cytokines will allow the immune system to be most useful or beneficial for the host. The production of IL-2 by helper T cells is also necessary for the proliferation of activated CD8+ T cells. [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. This cross-reliance on helper T cells is another way the immune system tries to prevent T cellmediated auto-immune disease. Understanding exactly how helper T cells respond to immune challenges is currently of major interest in immunology.development of various auto-immune diseases. because such knowledge may be very useful in the treatment of disease and in increasing the effectiveness of vaccination.

The upper. macrophage. interleukin-13 with Th1 cells. interleukinCytokines (Interleukin-2 was 5. interleukin 4 Type 1/ Th1 Main partner cell Macrophage type Type 2/ Th2 B-cell interferon-γ and tumor necrosis factor-beta. mø. interferon γ.Th1/Th2 Model for helper T cells. An antigen is ingested and processed by an APC. IL-4. The fragment is presented to it by MHC2. but this association may be . interleukin-6. interleukin-4. It presents fragments from it to T cells.[1] IFN-γ. IL-2. interleukinproduced classically associated 10. TGF-β. interleukin 2. Th0. transforming growth factor β. is a T helper cell.

Maximizes the killing Humoral immune system. IL-2 is produced by all helper T cells early in their activation.) interleukin10 production has been shown to be induced in activated Th1 cell[2] Cellular immune system. it is autoregulatory). and via positive feedback. Interleukin-4acts on helper T cells to promote the production of Th2 cytokines (including itself. and promoted + cytotoxic CD8 T cells. that decision is Other functions . The combined action of these two cytokines suggests that once the T cell has decided to produce these cytokines. an important cytokine The Type 2 response promotes its own profile using two different cytokines.misleading. IFN-gamma also inhibits the production of cytokines such as interleukin-4. to increase Also produces neutralizing antibody production. thereby promoting the Th1 profile. while interleukin10 (IL-10) inhibits a variety of cytokines includinginterleukin2 and IFN-γ in helper T cells and IL-12 in dendritic cells and macrophages. opsonizing antibodies The Type 1 cytokine IFN-γ increases the production of interleukin-12 by dendritic cells and macrophages. to induce Bstimulation proliferation of cell antibody class switching. efficacy of Stimulates B-cells into Immune themacrophages and the proliferation. IL-12 stimulates the production of IFN-γ in helper T cells.

associated with the Type preserved (and also encourages 2 response. along with less common cytokine profiles such as the Th3 subset of helper T cells. The presence of some cytokines (such as the ones mentioned above) will also influence the response that will eventually be generated. As such. but continues to stimulate plasma cells. hIL-10 is not believed to truly promote the Th2 response in humans. the Th2 cytokine IL-10 inhibits cytokine production of both Th subsets in humans. [edit]Limitations to the Th1/Th2 model The interactions between cytokines from the Th1/Th2 model can be more complicated in some animals. but acts to prevent overstimulation of helper T cells while still maximising the production of antibodies. we understand less about how the patterns themselves are decided. Other evidence suggests that the concentration of antigen presented to the T cell during primary activation influences its choice. but our understanding is nowhere near complete. ensuring that antibody production still occurs. and thus it other T cells to do the same). also acts to preserve its own response. There are also other types of T cells that can influence the expression and activation of helper T cells. Various evidence suggests that the type of APC presenting the antigen to the T cell has a major influence on its profile. While we know about the types of cytokine patterns helper T cells tend to produce. 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 regulatory T cells. For example. Human IL-10 (hIL-10) suppresses the proliferation and cytokine production of all T cells and the activity of macrophages. such as natural regulatory T cells. .

Both cytokines are inhibitory to helper T cells. and it is becoming clear that while the original Th1/Th2 model is enlightening and gives insight into the functions of helper T cells. TGF-β suppresses the activity of most of the immune system. and many cells express cytokines from both profiles. Th9 cells are claimed to be a IL9 . 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. T helper 17 cells (Th17)[3] has cast further doubt on the basic Th1/Th2 model. Recent scientific studies by Stockinger et al. The latter is a feature of Th3 cells. Some immunologists question the model completely. Both regulatory T cells and Th 3 cells produce the cytokine transforming growth factor-beta (TGF-β) and IL-10. These IL-17 producing cells were initially described as a pathogenic population implicated in autoimmunity but are now thought to have their own distinct effector and regulatory functions.One major difference between regulatory T cells and effector T cells is that regulatory T cells typically serve to modulate and deactivate the immune response. as some in vivo studies suggest that individual helper T cells usually do not match the specific cytokine profiles of the Th model. which transform into a regulatory subset after its initial activation and cytokine production. revealed that another T helper subset may exist. while effector T cell groups usually begin with immune-promoting cytokines and then switch to inhibitory cytokines later in their life cycle.[citation needed] That said. There is evidence to suggest that TGF-β may not suppress activated Th2 cells as effectively as it might suppress naive cells. The characterisation of another novel T helper subtype. Many of the cytokines in this article are also expressed by other immune cells (see individual cytokines for details). it is far too simple to define its entire role or actions. but it is not typically considered a Th2 cytokine.

In the worst case scenario. These reactions all involve IgE antibodies. eczema. such as corticosteroids and montelukast.[4] cell subset focused on [edit]Role of helper T cells in disease Considering the diverse and important role helper T cells play in the immune system. It's important to note that the numeral allocation of hypersensitivity "types" does not correlate . focus on suppressing mast cells or other allergic cells. When the immune system responds to very low levels of antigen that it usually shouldn't respond to. it is not surprising that these cells often influence the immune response against disease. Hypersensitivity reactions can be divided into four types:  Type 1 hypersensitivity includes common immune disorders such as asthma. a hypersensitivity response occurs. urticaria (hives) and anaphylaxis. They also appear to make occasional mistakes. which require a Th2 response during helper T cell development. T cells do not play a primary role during the actual inflammatory response. Fortunately this is a very rare occurrence. Preventative treatments. or generate responses that would be politely considered non-beneficial. the helper T cell response could lead to a disaster and the fatality of the host. allergic rhinitis (hay fever). Hypersensitivity is believed to be the cause of allergyand some auto-immune disease.(interleukin 9) producing T defending helminth infections. [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.

T cells play an important role in this hypersensitivity. are caused via the over-stimulation of immune cells. as they activate against the stimulus itself and promote the activation of other cells. Rhesus factor reactions during childbirth is a normal immune response against child antigens). resulting in chronic inflammation and cytokine release. and a similar  .(and is completely unrelated) "response" in the Th model. Type 4 hypersensitivity. commonly lymphocytes and macrophages. particularly macrophages via Th1 cytokines.  to the Type 2 and Type 3 hypersensitivity both involve complications from auto-immune or low affinity antibodies. 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. Other cellular hypersensitivities include cytotoxic T cell mediated auto-immune disease. also known as delayed type hypersensitivity. In both of these reactions. although some of these reactions under Type 2 hypersensitivity would be considered normal in a healthy immune system (for example. For example. Antibodies do not play a direct role in this allergy type. studies have suggested that lupus (SLE) and other auto-immune diseases of similar nature can be linked to the production of Th2 cytokines. T cells may play an accomplice role in generating these auto-specific antibodies.

HIV targets cells that express CD4. Helper T cells are required to fuel the development of these diseases. As a result. It has been proposed that during the non-symptomatic phase of HIV infection. The mechanism that killer T cells use during auto-immunity is almost identical to their response against viruses. [edit]HIV infection Perhaps the best example of the importance of CD4+ T cells is demonstrated with human immunodeficiency virus (HIV) infection. encouraging these cytotoxic cells to kill host cells in certain circumstances. dendritic cells (both groups express CD4 at low levels) and CD4+ T cells. transplant rejection. and can infect macrophages. Many auto-immune diseases are more complex. and the immune systembelieves. and this is supplied by CD4 T cells. This is initially compensated for via the production of new helper T cells from . and some viruses have been accused of causing auto-immune diseases such as Type 1 Diabetes mellitus. resulting in a slow kill rate of CD4+ T cells by the immune system. A well known example is rheumatoid arthritis. In order to create sufficient auto-reactive killer T cells. that a host antigen is foreign.phenomenon. where both antibodies and immune cells are known to play a role in the pathology. the virus has a relatively low affinity towards T cells (and has a higher affinity for macrophages). Generally the immunology of most auto-immune diseases is not well understood. the CD8+ T cells treat the host cell presenting that antigen as infected. interleukin-2 must be + + produced. transplant organ) that express that antigen. CD4 T cells can also stimulate cells such as natural killer cells and macrophages via cytokines such as interferon-gamma. Some of this section is a simplification. by mistake. Cellular auto-immune disease occurs because the host antigen recognition systems fail. and go on to destroy all host cells (or in the case of transplant rejection.

including HIV itself. CD4 T cell depletion during AIDS allows various pathogens to escape T cell recognition. Antibody class switching declines significantly once helper T cell function fails. Two components of the immune system are particularly affected in AIDS. it begins to infect CD4+ T cells far more efficiently (likely due to a change in the coreceptorsit binds to during infection). and accelerating the development of the disease. 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). eventually to a point where the CD4+ T cell population is too small to recognize the full range of antigens that could potentially be detected. thus allowing opportunistic infections that would normally elicit a helper T cell response to bypass the immune system. Once the virus becomes lymphotropic (or T-tropic) however. increasing the proliferation of the virus. The immune system loses its ability to . making AIDS patients very susceptible to most viruses. and the immune system is overwhelmed. The lack of full antigen cover results in the core symptoms of acquired immune deficiency syndrome (AIDS). due to its CD4+ T cell dependency: 1. functional CD4+ T cell levels begin to decrease. 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. At this point. 2. CD8+ T cells are not stimulated as effectively during the AIDS stage of HIV infection.the thymus (originally from the bone marrow).

especially in areas of the body not accessible by IgM antibodies. Indeed. If the patient does not respond to (or does not receive) HIV treatment they will succumb usually to either cancers or infections. by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function. expressed on monocytes and up-regulated upon monocytes activation. Another symptom of AIDS is the reduction in antibody levels due to a decrease in Th2 cytokines (and less interactions by helper T cells).improve the affinity of their antibodies.[5] . triggering PD-1. These effects are primarily due to the loss of any helper T cell that can interact with the B lymphocyte correctly. showed that inhibition of inhibition of CD4 T-cell expansion during HIV infection is also due to microbial translocation in an IL-10-dependent way. the immune system finally reaches a point where it is no longer coordinated or stimulated enough to deal with the disease. and are unable to generate B cells that can produce antibody groups such as IgG and IgA. Said et al. All of these complications result in an increased susceptibility to aggressive bacterial infections.

Sign up to vote on this title
UsefulNot useful