A T helper cell (sometimes also known as effector T cells or T_H 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. A lymphocyte is a type of white blood cell involved in the human bodys immune system. ... White blood cells (a. ... White Blood Cells is also the name of a White Stripes album. ... The immune system is the system of specialized cells and organs that protect an organism from outside biological influences. ... Cytotoxicity is the quality of being poisonous to cells. ... Phagocytosis (literally cell-eating) is a form of endocytosis wherein large particles are enveloped by the cell membrane of a (usually larger) cell and internalized to form a phagosome, or food vacuole. ... A pathogen (literally birth of pain from the Greek παθογένεια) is a biological agent that can cause disease to its host. ...

T_H 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. The immune system is the system of specialised cells and organs that protect an organism from outside biological influences. ... B cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response). ... T cells are a subset of lymphocytes that play a large role in the immune response. ... A bacteriocide or bactericide is a substance that kills bacteria and, preferably, nothing else. ... A phagocyte is a cell that ingests (and destroys) foreign matter, such as microorganisms or debris via a process known as phagocytosis, in which these cells ingest and kill offending cells by cellular digestion. ... Macrophages (Greek: big eaters) are cells found in tissues that are responsible for phagocytosis of pathogens, dead cells and cellular debris. ...

Mature T_H 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). CD4 (cluster of differentiation 4) is a molecule that is expressed on the surface of T helper cells (as well as regulatory T cells and dendritic cells). ... The immune system is the system of specialized cells and organs that protect an organism from outside biological influences. ... Human immunodeficiency virus, commonly known by the initialism HIV, formerly known as HTLV-III and lymphadenopathy-associated virus, is a retrovirus that primarily infects vital components of the human immune system such as CD4+ T cells, macrophages and dendritic cells. ... Acquired immunodeficiency syndrome, or Acquired Immune Deficiency Syndrome (or acronym AIDS or Aids), is a collection of symptoms and infections resulting from the specific damage to the immune system caused by infection with the human immunodeficiency virus (HIV). ...

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. T cells are a subset of lymphocytes that play a large role in the immune response. ... In human anatomy, the thymus is a ductless gland located in the upper anterior portion of the chest cavity. ... Lymph nodes are components of the lymphatic system. ... An antigen is a molecule that stimulates the production of antibodies. ... The T cell receptor or TCR is responsible for recognizing antigen bound to Major histocompatibility complex (MHC). ... It has been suggested that Class I MHC be merged into this article or section. ... CD4 (cluster of differentiation 4) is a molecule that is expressed on the surface of T helper cells (as well as regulatory T cells and dendritic cells). ... An antigen presenting cell (APC) is a cell that displays foreign antigen complexed with MHC on its surface. ... Dendritic cells (DC) are immune cells and form part of the mammal immune system. ... Macrophages (Greek: big eaters) are cells found in tissues that are responsible for phagocytosis of pathogens, dead cells and cellular debris. ... B cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response). ... Peptides are the family of molecules formed from the linking, in a defined order, of various amino acids. ...

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 antigenic peptides, which bind to either MHC Class I and Class II. Depending on the APC, some also express unprocessed antigen (e.g. for use in antibody class switching), such as follicular dendritic cells, however unprocessed antigens do not interact with T cells. T cells within the lymph nodes are exposed to these APCs and those that are capable of binding with antigen-bound MHC begin to activate. Memory T cells are also re-activated this way, if the body is re-infected with the same antigen. Dendritic cells (DC) are immune cells and form part of the mammal immune system. ...

CD4 is believed to be important for T_H 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 for interaction and activation. CD45 (or common leukocyte antigen) is also required for T cell activation, but the extracellular role (if any) of CD45 is not understood. Most proposals around CD45 isotypes suggest that it manipulates the accessability of the proteins between the cells. CD4 (cluster of differentiation 4) is a molecule that is expressed on the surface of T helper cells (as well as regulatory T cells and dendritic cells). ... Intercellular adhesion molecules (ICAMs) are molecules that promote adhesion between cells. ... In cell biology, molecular biology and related fields, the word extracellular means outside the cell. It is used in contrast to intracellular (inside the cell). ...

Verification

Once the naïve T cell has been exposed to antigen (a high affinity interaction between the TcR and the antigen-bound Class II MHC has occurred), the T cell then requires the activation of a second independant biochemical pathway. If the second signal does not exist, the T cell only recieves the first TcR/MHC signal and they become anergic; the cell will not respond to antigen in any future interaction even if both signals are present.

This signal requires an interaction between CD28 on the CD4+ T cell, and either protein CD80 (B7.1) or CD86 (B7.2) that is expressed on professional APC's. These proteins are known as co-stimulatory molecules, and is used to help confirm the source of the antigen/MHC complex that the T cell is interacting with. Since CD80/CD86 are only expressed on certain professional APC's at certain times, 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. The antigen CD28 is one of the molecules that provide co-stimulatory signals, which are required for T cell activation. ...

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 T_H cells, memory T_H cells, and suppressor T_H cells. The term cell growth is used in two different ways in biology. ... Interleukin-2 (IL2) is an interleukin, a type of biological response modifier that can improve the bodys natural response to disease. ...

• Effector T_H cells secrete cytokines, proteins or peptides that stimulate or interact with other leukocytes, including T_H cells.

• Memory T_H 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 T_H 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.

Cytokines are small protein molecules that regulate communication among immune system cells and between immune cells and those of other tissue types. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ... White Blood Cells is also the name of a White Stripes album. ... Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ...

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. In cell biology, molecular biology and related fields, the word extracellular means outside the cell. It is used in contrast to intracellular (inside the cell). ... Cytokines are small protein molecules that are the core of communication between immune system cells, and even between immune system cells and cells belonging to other tissue types. ...

T_H1/T_H2 Model for helper T cells

Proliferating helper T cells that develop into effector T cells differentiate into two major subtypes of cells known as T_H1 and T_H2 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. T_H1 cells produce interferon-gamma (or IFN-gamma) and lymphotoxin (also known as tumor necrosis factor-beta or TNF-beta), while T_H2 cells produce interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-13 (IL-13), among numerous other cytokines. The T_H1/T_H2 model also states that interleukin-12 (IL-12) plays an essential role during T_H1 development, but IL-12 is not produced by helper T cells, but rather by certain professional APCs, such as activated macrophages and dendritic cells. Interleukin-2 is associated with T_H1 cells, and its production by helper T cells is necessary for the proliferation of cytotoxic CD8+ T cells, but this association with T_H1 may be misleading; IL-2 is produced by all helper T cells early in their activation. Interferon-gamma or IFN-g is a dimerized soluble cytokine which is a Type II Interferon. ... Interleukin-4, abreviated IL-4, is a lymphokine that stimulates the proliferation of activated B-cells and T-cells, among other effects. ... Interleukin 12 (IL-12) is an interleukin that are naturally produced by macrophages and human B-lymphoblastoid cells (NC-37)in response to antigenic stimulation. ... Macrophages (Greek: big eaters) are cells found in tissues that are responsible for phagocytosis of pathogens, dead cells and cellular debris. ... Dendritic cells (DC) are immune cells and form part of the mammal immune system. ... Interleukin-2 (IL2) is an interleukin, a type of biological response modifier that can improve the bodys natural response to disease. ... CD8 (cluster of differentiation 8) is a molecule that is expressed on the surface of cytotoxic T cells. ...

Given the relative specificity of the cytokines released by either response on particular sections of the immune system it has been suggested that both T_H groups play separate roles during an immune response. That is; T_H1 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. T_H2 cells express many cytokines, many of which are essential in stimulating B-cells with antibody class switching and increased antibody production; T_H2 cells are therefore considered necessary for the full maturation of the humoral immune system. Macrophages (Greek: big eaters) are cells found in tissues that are responsible for phagocytosis of pathogens, dead cells and cellular debris. ... CD8 (cluster of differentiation 8) is a molecule that is expressed on the surface of cytotoxic T cells. ... B cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response). ... Humoral immunity is mediated by secreted antibodies, produced in cells of the B lymphocyte lineage (B cell). ...

This primary association between the cytokines of TH 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 T_H response; which is generally believed to have been primarily determined during the initial activation of the T cell. Eosinophil granulocyte Eosinophil granulocytes, commonly referred to as eosinophils (or less commonly as acidophils), are white blood cells that are responsible for combating infection by parasites in the body. ...

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 T_H2 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 T_H2 response promotes both the production of its own cytokines while inhibiting the establishment of the T_H1 response. Interleukin-4, abreviated IL-4, is a lymphokine that stimulates the proliferation of activated B-cells and T-cells, among other effects. ... Interleukin-10 (IL-10 or IL10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine, capable of inhibiting synthesis of pro-inflammatory cytokines like IFN-gamma, IL-2, IL-3, TNFα and GM-CSF by cells such as macrophages and Th1 cells. ... Interleukin-2 (IL2) is an interleukin, a type of biological response modifier that can improve the bodys natural response to disease. ... Interferon-gamma or IFN-g is a dimerized soluble cytokine which is a Type II Interferon. ...

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 T_H1 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. Interferon-gamma or IFN-g is a dimerized soluble cytokine which is a Type II Interferon. ... Interleukin 12 (IL-12) is an interleukin that are naturally produced by macrophages and human B-lymphoblastoid cells (NC-37)in response to antigenic stimulation. ... Interleukin-4, abreviated IL-4, is a lymphokine that stimulates the proliferation of activated B-cells and T-cells, among other effects. ...

Complexities surpassing the T_H model

The interactions between cytokines from the T_H1/T_H2 model can be more complicated in some animals. For example, the T_H2 cytokine IL-10 inhibits the cytokine production of both T_H 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. Plasma cells are B lymphocytes that secrete immunoglobulins (antibodies). ...

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 T_H3 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. Regulatory T cells (also known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self. ...

The major difference in definition of "suppressor" (or "natural regulatory") T cells is that they do not undergo change in cytokine function and are always immuno-suppressant, while other groups produce inhibitory cytokines later in its repertoire. The latter is a feature of T_H3 cells, which transform into a suppressor subset after its initial activation and cytokine production.

Both suppressor T cells and T_H3 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. Regulatory T cells (also known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self. ...

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 T_H1/T_H2 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 is the name given to a state in which an immune response damages the bodys own tissues. ... An allergy or Type I hypersensitivity is an immune system malfunction whereby a persons body is hypersensitised to react immunologically to typically nonimmunogenic substances. ... Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ...

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 T_H2 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 T_H model. For the play, see Hay Fever. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... Anaphylaxis is a severe and rapid systemic allergic reaction to a trigger substance, called an allergen. ... In physiology, corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. ...

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.

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 and once activated promote the activation of other cells, particularly macrophages via cytokines in the T_H1 response. A lymphocyte is a type of white blood cell involved in the human bodys immune system. ... Macrophages (Greek: big eaters) are cells found in tissues that are responsible for phagocytosis of pathogens, dead cells and cellular debris. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ...

Other cellular hypersensitivities include auto-reactive killer T cells and other cytotoxic cells. The importance of helper T cells in cell-mediated auto-immunity is relatively understood; interleukin-2 that is produced by CD4+ T cells is necessary for killer T cell proliferation. CD4+ T cells can also stimulate cells such as natural killer cells and macrophages that can also kill host cells. In such diseases, the T_H1 cytokines have been implicated in various autoimmune disorders as shown by elevated levels of IFN-gamma in tissues and from studies of IFN-gamma and IL-12 deficient mice. Conversely, T_H2-derived cytokines have been shown to inhibit cell-mediated auto-immune responses. A K cell (or a killer cell) is a lymphocyte with immunoglobulin Fc receptors, which allow it to bind to and kill antibody-coated cells by antibody-dependent cell-mediated cytotoxicity (ADCC). ... Cytotoxicity is the quality of being poisonous to cells. ... Interleukin-2 (IL2) is an interleukin, a type of biological response modifier that can improve the bodys natural response to disease. ... Natural killer cells (also known as NK cells, K cells, and killer cells) are a type of lymphocyte (a white blood cell) and a component of innate immune defense. ... Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ... Interferon-gamma or IFN-g is a dimerized soluble cytokine which is a Type II Interferon. ... Interleukin 12 (IL-12) is an interleukin that are naturally produced by macrophages and human B-lymphoblastoid cells (NC-37)in response to antigenic stimulation. ...

Many auto-immune diseases are more complex, such as rheumatoid arthritis, where both antibodies and immune cells play a role in the pathology, and generally the immunology of most auto-immune diseases is not well understood. Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. ...

Any direct role of helper T cells in humorally-derived auto-immunity is less clear, although studies have suggested that lupus (and other auto-immune diseases of similar nature) can be linked to the production of T_H2 cytokines.

Movement of activated helper T cells

Once helper T cells have proliferated and the response determined, the activated T_H cells leave the lymph node and transport through the lymphatic system and into the bloodstream. These cells then spread throughout the body, moving to inflamed tissues or other lymph nodes via chemotaxis. The mechanism by which immune cells cross the endothelium (lining of the blood vessels) is called diapedesis. Red blood cells (erythrocytes) are present in the blood and help carry oxygen to the rest of the cells in the body Blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). ... Chemotaxis is the phenomenon in which bodily cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. ... The endothelium is the layer of thin, flat cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. ... Diapedesis is the movement of leukocytes across the endothelial lining of blood vessels to interstitial fluid (IF). ...

Once in the site of infection/lymph nodes, helper T cells may bind to APCs expressing MHC Class II, and if it recognises the antigen bound to the MHC molecule, reactivates. Once reactivated, the T cell releases various products including cytokines discussed above, although it is likely that the cytokines it produces depends on its location, the cells interacting with it, the presence of other cytokines, as well as other factors that are not yet understood. Considering most infections involve most, or even all of the cell types CD4+ T cells interact with, the role of the helper T cell during infection is complex and yet to be fully elucidated.