T helper cells are a sub-group of lymphocytes, a type of
white blood cellWhite blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
, that play an important role in the
immune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected
hostIn biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...
cells or pathogens. Rather, they help other immune cells -- they activate and direct other immune cells. They are essential in
B cellB cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.
Mature T
h cells express the surface protein
CD4CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
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 systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. For example, when an antigen presenting cell expresses an antigen on
MHC class IIMHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
, a CD4
+ cell will aid those cells through a combination of cell to cell interactions (e.g. CD40 and CD40L) and through cytokines. Nevertheless, there are rare exceptions; for example, sub-groups of
regulatory T cellRegulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
s,
natural killer T cellNatural killer T cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self- and foreign lipids and glycolipids...
s, and cytotoxic T cells 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
HIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
, 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 (
AIDSAcquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
). There are also
some rare disordersLymphocytopenia, or lymphopenia, is the condition of having an abnormally low level of lymphocytes in the blood. Lymphocytes are a white blood cell with important functions in the immune system...
that result in the absence or dysfunction of CD4
+ T cells. These disorders produce similar symptoms, and many of these are fatal.
Activation of naïve helper T cells
Following T cell development, matured, naïve T cells leave the
thymusThe thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
and begin to spread throughout the body, including the lymph nodes. (Naïve T cells are those T cells that have never been exposed to the
antigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
that they are programmed to respond to.) Like all T cells, they express the
T cell receptorThe T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
-
CD3In immunology, the CD3 T-Cell Co-Receptor is a protein complex and is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with a molecule known as the T cell receptor and the ζ-chain to generate an activation...
complex. The T cell receptor (TcR) consists of both constant and variable regions. The variable region determines what antigen the T cell can respond to. CD4
+ T cells have TcRs with an affinity for Class II MHC, and CD4 is involved in determining MHC affinity during maturation in the
thymusThe thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
. Class II MHC proteins are generally only found on the surface of specialised antigen-presenting cells (APCs). Specialised antigen presenting cells are primarily dendritic cells, macrophages and B cells, although B 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 cellsFollicular dendritic cells are cells of the immune system found in lymph follicles of secondary lymphoid organs and tertiary lymphoid organs. They are probably not of hematopoietic origin, though they look similar to true dendritic cells due to their filiform dendritic processes, but are of...
, 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.
Recognition (Signal 1)
During an immune response, professional antigen-presenting cells (APCs)
endocytoseEndocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
(absorb) foreign material (typically
bacteriaBacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
or
virusA virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es), which undergoes
processingAntigen processing is a biological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. This process involves two distinct pathways for processing of antigens from an organism's own proteins or intracellular pathogens , or from phagocytosed...
, then travels from the infection site 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 the specific TCRs against the peptide/MHC complex to activate.
When a T
h cell encounters and recognises the antigen, on an APC, the
TCRThe T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
-CD3 complex binds strongly to the peptide-MHC complex present on the surface of professional APC's.
CD4CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
, a co-receptor of the TCR complex, also binds to a different section of the MHC molecule. These interactions bring these proteins closer together, allowing the
intracellularNot to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
kinaseIn chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s present on the TCR, CD3 and CD4 proteins to activate each other via
phosphorylationPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
. With the assistance of a phosphatase present on the intracellular section of
CD45Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene. PTPRC is also known as CD45 antigen , which was originally called leukocyte common antigen.- Function :The protein encoded by this gene is a member of the protein tyrosine...
(common leukocyte antigen), these molecules activate the major biochemical pathways in the
cytosolThe cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
of the T
h cell. These active pathways are known as Signal 1 of T cell activation, as it is the first and primary pro-activation signal in a T
h cell. Upon subsequent encounters with a given antigen,
memory T cellsMemory T cells are a subset of infection- as well as potentially cancer-fighting T cells that have previously encountered and responded to their cognate antigen; thus, the term antigen-experienced T cell is often applied. Such T cells can recognize foreign invaders, such as bacteria or viruses,...
are re-activated using the same TCR pathways.
The binding of the antigen-MHC to the TCR complex and CD4 may also help the APC and the T
h cell adhere during T
h cell activation, but the integrin protein
LFA-1Lymphocyte function-associated antigen 1, also known as LFA-1 is found on all T-cells and also on B-cells, macrophages and neutrophils and is involved in recruitment to the site of infection. It binds to ICAM-1 on antigen-presenting cells and functions as an adhesion molecule. LFA-1 is the first...
on the T cell and
ICAMIntercellular adhesion molecules are members of the family of cell adhesion molecules. They include the following:* ICAM-1 * ICAM2* ICAM3* ICAM4* ICAM5...
on the APC are the primary molecules of adhesion in this cell interaction.
It is unknown what role the relatively bulky extracellular region of CD45 plays during cell interactions, but CD45 has various isoforms that change in size depending on the T
h cell's activation and maturation status. For example, CD45 shortens in length following T
h activation (CD45RA
+ to CD45RO
+), 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, thereby necessitating an increase in the affinity (and specificity) of the T cell for activation. Once the activation has occurred however, CD45 shortens, allowing easier interactions and activation as an effector T helper cell.
Verification (Signal 2)
Having received the first TcR/CD3 signal, the naïve T cell must activate a second independent biochemical pathway, known as Signal 2. This verification step is a protective measure to ensure that a T cell is responding to a foreign antigen. If this second signal is not present during initial antigen exposure, the T cell presumes that it is auto-reactive. This results in the cell becoming
anergicAnergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal...
(anergy is generated from the unprotected biochemical changes of Signal 1). 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 throughout the body with no value until they
apoptoseApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
at the end of their lifespan.
The second signal involves an interaction between
CD28CD28 is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 and CD86 . When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells...
on the CD4
+ T cell and the proteins
CD80Cluster of Differentiation 80 is a protein found on activated B cells and monocytes that provides a costimulatory signal necessary for T cell activation and survival...
(B7.1) or
CD86Cluster of Differentiation 86 is a protein expressed on antigen-presenting cells that provides costimulatory signals necessary for T cell activation and survival...
(B7.2) on the professional APCs. Both CD80 and CD86 activate the CD28 receptor. These proteins are also known as
co-stimulatory moleculesDuring the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.- Co-stimulation T cells require :...
.
Although the verification stage is necessary for the activation of naïve helper T cells, the importance of this stage is best demonstrated during the similar activation mechanism of CD8
+ cytotoxic T cellA cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
s. As naïve CD8
+ T cells have no true bias towards foreign sources, 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). CD28 plays an important role in decreasing the risk of T cell auto-immunity against host antigens.
Once the naïve T cell has both pathways activated, the biochemical changes induced by Signal 1 are altered, allowing the cell to activate instead of anergise. The second signal is then obsolete; only the first signal is necessary for future activation. This is also true for memory T cells, which is one example of learned immunity. Faster responses occur upon reinfection because memory T cells have already undergone confirmation and can produce effector cells much sooner.
Proliferation
Once the two-signal activation is complete the T helper cell (T
h) then allows itself to
proliferateThe term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
. It achieves this by releasing a potent T cell growth factor called
interleukin 2Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
(IL-2) which acts upon itself in an autocrine fashion. Activated T cells also produce the alpha sub-unit of the IL-2 receptor (
CD25CD25 is the alpha chain of the IL-2 receptor. It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes that associates with CD122 to form a heterodimer that can act as a high-affinity receptor for IL-2.CD25 is...
or IL-2R), enabling a fully functional receptor that can bind with IL-2, which in turn activates the T cell's proliferation pathways.
The autocrine or paracrine secretion of IL-2 can bind that same T
h cell or neighboring T
h's via the IL-2R thus driving proliferation and clonal expansion. The T
h cells receiving both signals of activation will then become T
h0 cells (T helper 0) cell that secrete IL-2,
IL-4Interleukin-4, abbreviated IL-4, is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified, but recent...
and interferon gamma (IFN-γ). The T
h0 cells will then differentiate into T
h1 or T
h2 cells depending on
cytokineCytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
environment. IFN-γ drives T
h1 cell production while
IL-10Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
and IL-4 inhibit T
h1 cell production. Conversely, IL-4 drives T
h2 cell production and IFN-γ inhibits T
h2 cells. It should be noted that these cytokines are pleiotropic and carry out many other functions of the immune response.
Maturation
After many cell generations, the T
h cell's progenitors differentiate into
effector Th cells,
memory Th cells, and
regulatory Th cells.
- Effector Th cells secrete cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s, proteinProteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s or peptidePeptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s that stimulate or interact with other leukocytes, including Th cells.
- 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).
- Regulatory T cell
Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
s 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 have been shown to 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 cellsA cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
. Without helper T cell interactions,
CD8CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
+ T cells do not develop effector function and eventually undergo
apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. This cross-reliance on helper T cells is another way the immune system works to prevent T cell-mediated auto-immune disease.
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
extracellularIn cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
signals such as
cytokineCytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s) 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
immunologyImmunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
, because such knowledge may be very useful in the treatment of
diseaseA disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
and in increasing the effectiveness of
vaccinationVaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...
.
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 T
h1 and T
h2 cells (also known as Type 1 and Type 2 helper T cells, respectively).
| |
Type 1/ Th1 |
Type 2/ Th2
>-
| Main partner cell type |
Macrophage Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
|
|
>-
| Cytokines produced
interferon-γ and tumor necrosis factor-beta. (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.) interleukin-10 production has been shown to be induced in activated Th1 cell |
|
>-
| Immune stimulation promoted
Cellular immune system Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...
. Maximizes the killing efficacy of the macrophages and the proliferation of cytotoxic CD8CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
+ T cells. Also produces opsonizing antibodies |
antibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
production.
>-
| Other functions |
The Type 1 cytokine IFN-γ Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
increases the production of interleukin-12 by dendritic cells and macrophages, and via positive feedback, IL-12 stimulates the production of IFN-γInterferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
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 with the Type 2 response, and thus it also acts to preserve its own response. |
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 IFN-γ Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
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). |
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.
Limitations to the Th1/Th2 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-10Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
inhibits cytokine production of both T
h subsets in humans. Human IL-10 (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 T
h2 response in humans, but acts to prevent over-stimulation of helper T cells while still maximising the production of
antibodiesAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
.
There are also other types of T cells that can influence the expression and activation of helper T cells, such as natural regulatory 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 regulatory T cells.
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, while effector T cell groups usually begin with immune-promoting cytokines and then switch to inhibitory cytokines later in their life cycle. The latter is a feature of T
h3 cells, which transform into a regulatory subset after its initial activation and cytokine production.
Both regulatory T cells and T
h3 cells produce the cytokine transforming growth factor-beta (TGF-β) and IL-10. Both cytokines are inhibitory to helper T cells; TGF-β suppresses the activity of most of the immune system. There is evidence to suggest that TGF-β may not suppress activated Th2 cells as effectively as it might suppress naive cells, but it is not typically considered a Th2 cytokine.
The characterisation of another novel T helper subtype,
T helper 17 cellT helper 17 cells are a subset of T helper cells producing interleukin 17 discovered in 2007. They are considered developmentally distinct from Th1 and Th2 cells and excessive amounts of the cell are thought to play a key role in autoimmune disease such as multiple sclerosis , but also...
s (T
h17) has cast further doubt on the basic T
h1/T
h2 model. These
IL-17Interleukin-17 is the founding member of a group of cytokines called the IL-17 family. IL-17A, was originally identified as a transcript from a rodent T-cell hybridoma by Rouvier et al. in 1993...
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. Of note, recent evidence suggest that functional plasticity is an intrinsic capacity of T helper cells. Indeed, a study in mice demonstrated that T
h17 cells transform into T
h1 cells
in vivo. A subsequent study furthermore showed that extensive T helper cell plasticity is also prominent in man.
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 T
h1/T
h2 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 T
h model, and many cells express cytokines from both profiles. That said, the T
h 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.
Recent scientific studies by Stockinger et al. revealed that another T helper subset may exist. Th9 cells are claimed to be a IL9 (
interleukin 9Interleukin 9, also known as IL9, is a cytokine belonging to the group of interleukins.-Further reading:...
) producing T cell subset focused on defending helminth infections.
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.
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
hypersensitivityHypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
response occurs. Hypersensitivity is believed to be the cause of
allergyAn Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
and some auto-immune disease.
Hypersensitivity reactions can be divided into four types:
- Type 1 hypersensitivity includes common immune disorders such as asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, allergic rhinitisAllergic rhinitis, also known as pollenosis or hay fever, is an allergic inflammation of the nasal airways.It occurs when an allergen, such as pollen, dust or animal dander is inhaled by an individual with a sensitized immune system...
(hay fever), eczemaEczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
, urticariaUrticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
(hives) and anaphylaxisAnaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
. These reactions all involve IgEIGE was one of the largest services company buying and selling virtual currencies and accounts for MMORPG. During its peak time, it had offices in Los Angeles, China , and headquarters & customer service centre in Hong Kong. IGE was one of the main monopoly in virtual economy services, also known...
antibodiesAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
, which require a Th2 response during helper T cell development. Preventative treatments, such as corticosteroids and montelukastMontelukast is a leukotriene receptor antagonist used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It is usually administered orally...
, 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
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
(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
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
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 cellA cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
mediated auto-immune disease, and a similar phenomenon;
transplant rejectionTransplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
. Helper T cells are required to fuel the development of these diseases. In order to create sufficient
auto-reactiveAutoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
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 cellNatural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
s and macrophages via cytokines such as
interferon-gammaInterferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
, 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 mellitusDiabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
. Cellular auto-immune disease occurs because the host antigen recognition systems fail, and the
immune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
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.
Some of this section is a simplification. Many auto-immune diseases are more complex. A well known example is
rheumatoid arthritisRheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, 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+CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
T cells is demonstrated with
human immunodeficiency virusHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
(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 is initially compensated for via the production of new helper T cells from the
thymusThe thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
(originally from the
bone marrowBone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
). 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-receptorA co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.-Co-receptor Properties:...
s 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 recognize the full range of
antigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s that could potentially be detected. The lack of full antigen cover results in the core symptoms of acquired immune deficiency syndrome (
AIDSAcquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
). CD4 T cell depletion during AIDS allows various pathogens to escape T cell recognition, thus allowing
opportunistic infectionAn opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system...
s 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
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
+ T cells are not stimulated as effectively during the AIDS stage 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 its ability to improve the affinity of their antibodies, and are unable to generate B cells that can produce antibody groups such as IgG and IgA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
. These effects are primarily due to the loss of any helper T cell that can interact with the B lymphocyte correctly. Another symptom of AIDS is the reduction in antibody levels due to a decrease in 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 IgMIGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
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.
Said et al. showed that inhibition of CD4 T-cell expansion during HIV infection is also due to microbial translocation in an IL-10-dependent way. Indeed, triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.
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