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Gamma delta T cell

Gamma delta T cells (γδ T cells) are T cells that have a distinctive T-cell receptor (TCR) on their surface. Most T cells are αβ (alpha beta) T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, gamma delta (γδ) T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

The antigenic molecules that activate gamma delta T cells are still largely unknown. However, γδ T cells are peculiar in that they do not seem to require antigen processing and major-histocompatibility-complex (MHC) presentation of peptide epitopes, although some recognize MHC class Ib molecules. Furthermore, γδ T cells are believed to have a prominent role in recognition of lipid antigens. They are of an invariant nature and may be triggered by alarm signals, such as heat shock proteins (HSP).

There also exists a γδ-T-cell sub-population within the epidermal compartment of the skin of mice. Originally referred to as Thy-1+ dendritic epidermal cells (Thy1+DEC), these cells are more commonly known as dendritic epidermal T cells (DETC). DETCs arise during fetal development and express an invariant and canonical Vγ3 Vδ1 T-cell receptor (using Garman nomenclature).

Contents

The conditions that lead to responses of gamma delta T cells are not fully understood, and current concepts of them as 'first line of defense', 'regulatory cells', or 'bridge between innate and adaptive responses' only address facets of their complex behavior. In fact, gamma delta T cells form an entire lymphocyte system that develops under the influence of other leukocytes in the thymus and in the periphery. When mature, they develop into functionally distinct subsets that obey their own (mostly unknown) rules and have countless direct and indirect effects on healthy tissues and immune cells, pathogens and tissues enduring infections, and the host responses to them.

Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, gamma delta T cells exhibit several characteristics that place them at the border between the more evolutionarily primitive innate immune system that permits a rapid beneficial response to a variety of foreign agents and the adaptive immune system, where B and T cells coordinate a slower but highly antigen-specific immune response leading to long-lasting memory against subsequent challenges by the same antigen.

Gamma delta T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and can develop a memory phenotype. However, the various subsets may also be considered part of the innate immunity in which a specific TCR can function as a pattern recognition receptor. For example, according to this paradigm, large numbers of (human) Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted intraepithelial Vδ1 T cells will respond to stressed epithelial cells bearing sentinels of danger.

Recent work has shown that human Vγ9/Vδ2 T cells are also capable of phagocytosis, a function previously exclusive to innate myeloid lineage cells such as neutrophils, monocytes and dendritic cells This provides further evidence that the biology of gamma delta T cells spans both innate and adaptive immune responses.

Recently, it was believed that γδ17 T cells were only able to produce IL-17 in acute infections. It was recently discovered that γδ17 T cells can produce IL-17 even when the immune response is not induced. These cells are likely to be generated from fetal γδ thymocytes and as they egress from the thymus, they will progress to non-lymphoid tissues such as lungs, peritoneal cavity, dermis, tongue and uterus.

The γδ17 T that will accumulate in the adipose tissue (dermis) will not only controls the homeostasis of regulatory T cells but also an adaptive thermogenesis, therefore they are able to control the maintenance of core body temperature. Using aging mice as a model, the molecular and cellular mechanisms that act under thermoneutrality circumstances (steady state) or after cold exposure has been recently acknowledged,

When the mice is on a steady state, IL-17 produced by the γδ17 T cells will stimulate stromal cells expressing the IL-17 receptor to produce IL-33 in vivo, and therefore provide a molecular link to T reg cells expressing the IL-33 receptor ST2 in the adipose tissue, so ST2+ Treg cells will accumulate and this will lead to the maintenance of the tissue homeostasis. This recent finding explains the mechanism of why the number of T reg cells continuously increases during aging. On the other hand, it has been shown that after exposing the mice to cold, the production of TNF and IL-17 will act on the adipocytes uncoupling the protein UCP1, which is required for inducing a UCP1-dependent thermogenic program.

Autoimmune disease results from abnormal response of immune system. Production of autoantibodies or autoreactive T cells is present during such disease. The role of γδ T cell in autoimmune disease is to help B cells to produce autoantibodies, through proinflammatory cytokines. IL-17A is important for development and progression of autoimmune diseases. Main sources are Th17 CD4+ αβ T cells, but γδ T cell subset plays role in autoimmune pathogenesis and regulation, too, because they contribute to production of IL-17A and other chemokines. They also interact with other innate and adaptive immune cells and modulate their functions. γδ T cell enhance or suppress inflammation, depending on the site and stage of disease. They rise from periphery and can be accumulated in inflamed tissue. These T cells can become active without TCR ligand – they can induce inflammation in autoimmune diseases very fast.

γδ T cells have clinical association with many autoimmune diseases.

Idiopathic bowel diseases IBD

γδ T cells are a major T cell subset of intraepithelial lymphocytes (IEL) present in the epithelial layer of mucosa. They regulate immunosuppressive functions of IELs and play role in development of tolerance. These so-called protective γδ T cells promote tissue repair and cell healing. Pathogens and other inflammation stimuli cause production of retinoic acid by dendritic cells, it induces γδ T cells to produce IL-22. This cytokine is responsible for cell-mediated production of antimicrobial peptides and tissue repair.

On the other hand, pathogenic γδ T cells produce IL-17. This cytokine induces Th17 cells differentiation, and dendritic cell- mediated production of IL-12 and IL-23 promotes differentiation of Th17 cells to Th1 cells, which produce IFN‐γ. Matrix metalloproteinases and NO present in inflamed tissue damage and degrade basal membrane, leading to development of IBD.

Type 1 diabetes T1D

T1D is an autoimmune disease where β cells of the pancreas, which produce insulin, are damaged by autoreactive T cells. There is infiltration of both innate and adaptive immune cells in pancreas. Studies on mice showed that γδ T cells play a role in T1D pathogenesis. They infiltrate islets and may even co-operate with αβ T cells to induce T1D.

Rheumatoid arthritis RA

RA is a chronic autoimmune disease caused by accumulation of self-reactive T cells, which are induced by inflammation in synovial fluid and joints. RA patients have higher numbers of γδ T cells producing IL-17. It leads to production of inflammatory cytokines by neutrophils, macrophages and fibroblasts, and RANKL by osteoblasts (RANKL causes conversion of precursors into osteoclasts). Matrix metalloproteinases and cathepsins induced by inflammatory cytokines, together with RANKL, cause bone and cartilage erosion, which leads to RA development.

Multiple sclerosis MS

γδ T cells are involved in development of this autoimmune disease. They are cytotoxic against oligodendrocytes, cells that participate in the myelinization of axons. Patients have increased numbers of γδ T cells in brain and cerebrospinal fluid, and these cells accumulate in demyelinated areas of CNS and make plaques. In the mice models, different subsets of γδ T cells were identified. The most abundant were the ones producing IL-17. IL-17 induces Th17 cells and Th17 response.

Psoriasis

Psoriasis is one of the autoimmune diseases in which the γδ T cells together with Th1 and Th17 play an essential role in the disease development. In response to IL-23, the adipose gamma T cells will produce IL-17, and this interleukin promotes development and progression of psoriasis. Also it has been proven that Vγ9Vδ2 T cells in patients suffering from Psoriasis participate in the development of the disease. The number of Vγ9Vδ2 T cells increase in the skin lesions of psoriasis patients but decreased in the blood. This finding indicates redistribution of Vγ9Vδ2 T cells from the blood to the skin compartment in psoriasis. The psoriasis severity is associated with lower level of γ9Vδ2 T cells in the circulation, therefore a successful anti-psoriatic therapy leads to increase of peripheral Vγ9Vδ2 T cells. The major outcome is that the measurement of these cells in blood and skin lesions can be used as a marker in order to follow-up the psoriasis progression.

Non-MHC restricted recognition of antigens and high cytokine secretion of γδ T cells suggest that these cells would be effective in cancer immunotherapy. Trials in numerous cancers (renal carcinoma, leukemia, lung cancer) showed that they are tolerated and safe, but on the other hand, there are reports saying that γδ T cells cause cancer development for example through production of IL-17 in tumor microenvironment, which promotes angiogenesis and cell growth or because their ability to increase numbers of myeloid derived suppressor cells. Therefore the effectiveness of immunotherapy based on γδ T cells is limited.

γδ T cells can be divided into two groups: effector and regulatory γδ T cells:

Effector functions of γδ T cells

After infiltrating tumor as a response to chemokines produced by monocytes and macrophages, γδ T cells interact with stress-induced molecules on tumor cells and secrete cytotoxic molecules, inflammatory cytokines and activate adaptive immunity cells. They can also lyse tumor cells by antibody‐dependent cellular cytotoxicity (ADCC) (through binding Fc region of IgG deposited on tumor cells). γδ T cells secrete IFN-γ and IL-17, which leads to higher expression of MHC-I, positive regulation of cytotoxic T lymphocytes and induction of anti-tumor response. γδ T cells also interact with DCs and develop Th1 response.

Regulatory functions of γδ T cells

Besides effector functions, γδ T cells have regulatory and suppressive role in the tumor microenvironment through expression of transcription factors (FoxP3, Helios) and CD86-CTLA-4 interaction between APCs and γδ T cells. They also impair effector immune cells (DC, NK, iNKT, CD8+ T cells) through IL-4, IL-10 and TGF-β. Also IL-17 secreted by γδ T cells has pro-tumorogenic role (enhanced angiogenesis, recruitment of macrophages, expansion and polarization of neutrophils and their suppression of CD8+ T cells).

Laboratory mice (Mus musculus)

Mouse Vγ chains

This table summarizes the nomenclature of mouse Vγ chains and indicates monoclonal antibodies often used to identify these chains. This system has been best described in strain C57BL/6 and might not apply well to other strains. There are two systems of nomenclature in use (Heilig; Garman), and many writers do not indicate which system they use. For example, the IMGT (International Immunogenetics Information System) uses the Heilig notation, but does not indicate this fact on its website.[citation needed] This table refers to variable chain Vγ gene segments and to monoclonal antibodies that detect the corresponding Vγ protein chains. Note that Adrian Hayday's proposed nomenclature is not widely used,[citation needed] leaving considerable confusion in the literature. One advantage and weakness of the Hayday nomenclature is that it is based on the gene order in the B6 genome, but this might not apply to other strains.

Heilig and Tonegawa's
system
Garman's system
"Hayday's system" antibodies comments
Vγ5 Vγ3 GV1S1 536; 17D1 specific for Vγ5(Heilig)+Vδ1 clonotype Skin, Jγ1Cγ1
Vγ6 Vγ4 GV2S1 17D1; can detect Vγ6Vδ1 when pretreated with GL3 antibodies reproductive mucosa;Jγ1Cγ1
Vγ4 Vγ2 GV3S1 UC310A6 lung;Jγ1Cγ1
Vγ7 Vγ5 GV4S1 F2.67 Pereira most common form in intestinal IEL
orthologous to human Vγ1
Jγ1Cγ1
Vγ1 Vγ1.1 GV5S1 2.11 Pereira 1995 peripheral lymphoid tissues;Jγ4Cγ4
Vγ2 Vγ1.2 GV5S2 Jγ1Cγ1
Vγ3 Vγ1.3 GV5S3 Jγ3-pseudoCγ3
Mouse Vgamma locus for C57BL/6 genome; drawn to scale. Chromosome 13: 1.927 to 1.440 Megabp Heilig notation

Human forms

Human Vδ2+ T cells

Vγ9/Vδ2 T cells are unique to humans and primates and represent a minor and unconventional constituent of the leukocyte population in peripheral blood (0.5-5%), yet they are assumed to play an early and essential role in sensing 'danger' by invading pathogens as they expand dramatically in many acute infections and may exceed all other lymphocytes within a few days, e.g. in tuberculosis, salmonellosis, ehrlichiosis, brucellosis, tularemia, listeriosis, toxoplasmosis, and malaria.

Of note, all Vγ9/Vδ2 T cells recognize the same small microbial compound (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a natural intermediate of the non-mevalonate pathway of isopentenyl pyrophosphate (IPP) biosynthesis. HMB-PP is an essential metabolite in most pathogenic bacteria including Mycobacterium tuberculosis and malaria parasites, but is absent from the human host. Bacterial species that lack the non-mevalonate pathway and synthesize IPP via the classical mevalonate pathway instead, such as Streptococcus, Staphylococcus, and Borrelia, are unable to produce HMB-PP and do not specifically activate Vγ9/Vδ2 T cells.

IPP itself is structurally closely related to HMB-PP and ubiquitously present in all living cells (including human cells), yet its potency in vitro is reduced 10,000-fold; whether IPP represents a physiological 'danger' signal of stressed or transformed cells is still unclear. Of pharmacological interest and with bioactivities comparable to that of IPP are synthetic aminobisphosphonates such as zoledronate (Zometa) or pamidronate (Aredia), that are widely used to treat osteoporosis and bone metastases, and incidentally act as Vγ9/Vδ2 T cell receptor agonists. However, increasing evidence suggests that these aminobisphosphonate 'antigens' are not recognised directly by Vγ9/Vδ2 T cells and in fact act indirectly, via their effects on the mevalonate biosynthetic pathway, leading to an accumulation of IPP. Finally, certain alkylated amines have been described to activate Vγ9/Vδ2 T cells in vitro, however only at millimolar concentrations, i.e. with potencies 106-108-fold lower than those of HMB-PP, thereby raising questions about their physiological relevance.

It is still not clear whether these non-peptidic antigens bind directly to the Vγ9/Vδ2 TCR or if a presenting element exists. There is evidence for a requirement for a species-specific cell-cell contact. However, none of the known antigen-presenting molecules like MHC class I and II or CD1 are required for γδ T cell activation suggesting the existence of a novel presenting element. Strong support for a direct recognition of non-peptide antigens by the Vγ9/Vδ2 TCR comes from studies which demonstrated that a transfected Vγ9/Vδ2 TCR can confer responsiveness onto a hitherto unresponsive cell; furthermore, antibodies to the γδ TCR block recognition. Thus, the presence of a functional Vγ9/Vδ2 TCR appears mandatory for a response to non-peptidic antigens although the basis for the huge differences in bioactivity between closely related molecules like HMB-PP and IPP cannot be explained by conventional epitope presentation/recognition models.

These Vγ9Vδ2 T cells can also behave like professional antigen-presenting cells (APC). It seems that human Vγ9Vδ2 T cells are characterized by a specific inflammatory migration program, including multiple receptors for inflammatory chemokines (CXCR3, CCR1, CCR2 and CCR5). It means that the stimulation with IPP or HMB-PP induces migration to the lymphatic tissues, specifically to the T cell area of lymph nodes. So the stimulation of Vγ9Vδ2 T cells with phosphoantigens results in expression of multiple markers which are associated with APC, like MHC I and II molecules, co-stimulatory molecules (CD80, CD86) and adhesion receptors (CD11a, CD18, CD54). Thus activated Vγ9Vδ2 T cells behave like APCs (γδ T-APC) and present antigens to αβ T cells. This leads to turn of naïve CD4+ and CD8+ αβ T cells into effector cells. The differentiation, induced by γδ T-APC, most often led to T helper cell response, in the most of cases to pro-inflammatory Th1 response with subsequent production of IFN-γ and TNF-α. But in the case of a low γδ T-APC: CD4+ ratio it leads to differentiation of some naïve αβ T cells into Th2 (IL-4) or Th0 (IL-4 plus IFN-γ) cells. Human Vγ9Vδ2 T cells are also cells with excellent antigen cross-presentation activity, a process describing the uptake of exogenous antigen and its routing to the MHC I pathway for induction CD8+ cytotoxic T cells. Thus activated cytotoxic T cells can effectively kill infected or tumor cells. This fact can be used in the immunotherapy of cancer and infectious diseases.

Human non-Vδ2+ T cells

The extensive structural diversity of Vδ1 and Vδ3 TCRs and the existence of Vδ1+ clones reactive against MHC, MHC-like, or non-MHC molecules suggest recognition of a highly diverse and heterogeneous set of antigens by non-Vδ2 cells, although cognate interactions between non-Vδ2 TCRs and any of these antigens have not been shown yet. MHC class-I-chain-related gene A (MICA) has also been proposed as an important tumor antigen recognized by Vδ1+ T cells. However, the very low affinity of MICA–Vδ1 TCR interactions estimated by surface plasmon resonance analyses raises doubts about the functional relevance of MICA or MHC class-I-chain-related gene B (MICB) recognition by Vδ1+ TCRs.

Non-Vδ2 γδ T cells are expanded in various infectious contexts involving intracellular bacteria (Mycobacteria and Listeria) as well as extracellular bacteria, such as Borrelia burgdorferi and viruses (HIV, cytomegalovirus). In most instances, the stimuli that trigger Vd1 expansion are not derived from pathogens but instead correspond to endogenous gene products presumably upregulated on infection. The antigens recognized by non-Vδ2 T cells expanded in the above infectious contexts have not been characterized, but the fact that Vδ1+ T-cell responses are not blocked by monoclonal antibody directed against known classical or non-classical MHC molecules suggests recognition of a new class of conserved stress-induced antigens. A recent study of primary cytomegalovirus infection in infants found increased Vδ1 T cells that also expressed the typically NK cell associated markers NKG2C and CD57

A recent study has identified a specific subset of gut-resident Vδ1 IELs (intraepithelial lymphocytes) which express high levels of a natural cytotoxic receptor (NCR) which is NKp46. These receptors are expressed almost exclusively by natural killer (NK) cells and play a central role in triggering their activation, but it has been described that γδ T cells can express these receptors. These cells are named NKp46+/Vδ1 IELs.

The major outcome of this study is the clinical relevance of this cells, which can be used a prognostic marker in the colorectal cancer (CRC), in order to follow-up its progression. Lower frequencies of NKp46+/Vδ1 IELs in healthy intestinal tissues surrounding the tumor mass, associate with a higher tumor progression and metastasis. It is acknowledged that this subset can control the metastasis, so the higher levels of this population, the less probabilities for the tumor to progress and proliferate to other tissues.

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Gamma delta T cell
Gamma delta T cell Language Watch Edit 160 160 Redirected from Gd T cells Gamma delta T cells gd T cells are T cells that have a distinctive T cell receptor TCR on their surface Most T cells are ab alpha beta T cells with TCR composed of two glycoprotein chains called a alpha and b beta TCR chains In contrast gamma delta gd T cells have a TCR that is made up of one g gamma chain and one d delta chain This group of T cells is usually less common than ab T cells but are at their highest abundance in the gut mucosa within a population of lymphocytes known as intraepithelial lymphocytes IELs 1 The antigenic molecules that activate gamma delta T cells are still largely unknown However gd T cells are peculiar in that they do not seem to require antigen processing and major histocompatibility complex MHC presentation of peptide epitopes although some recognize MHC class Ib molecules Furthermore gd T cells are believed to have a prominent role in recognition of lipid antigens They are of an invariant nature and may be triggered by alarm signals such as heat shock proteins HSP There also exists a gd T cell sub population within the epidermal compartment of the skin of mice Originally referred to as Thy 1 dendritic epidermal cells Thy1 DEC 2 these cells are more commonly known as dendritic epidermal T cells DETC DETCs arise during fetal development and express an invariant and canonical Vg3 Vd1 T cell receptor using Garman nomenclature 3 Contents 1 Gamma delta T cells in innate and adaptive immunity 2 Gamma delta T cells in murine thermogenesis 3 Gamma delta T cells in autoimmunity 3 1 Idiopathic bowel diseases IBD 3 2 Type 1 diabetes T1D 3 3 Rheumatoid arthritis RA 3 4 Multiple sclerosis MS 3 5 Psoriasis 4 Gamma delta T cells and cancer 4 1 Effector functions of gd T cells 4 2 Regulatory functions of gd T cells 5 Gene families in different species 5 1 Laboratory mice Mus musculus 5 1 1 Mouse Vg chains 5 2 Human forms 5 2 1 Human Vd2 T cells 5 2 2 Human non Vd2 T cells 6 See also 7 References 8 Further reading 9 External linksGamma delta T cells in innate and adaptive immunity EditThe conditions that lead to responses of gamma delta T cells are not fully understood and current concepts of them as first line of defense regulatory cells or bridge between innate and adaptive responses 1 only address facets of their complex behavior In fact gamma delta T cells form an entire lymphocyte system that develops under the influence of other leukocytes in the thymus and in the periphery When mature they develop into functionally distinct subsets that obey their own mostly unknown rules and have countless direct and indirect effects on healthy tissues and immune cells pathogens and tissues enduring infections and the host responses to them Like other unconventional T cell subsets bearing invariant TCRs such as CD1d restricted Natural Killer T cells gamma delta T cells exhibit several characteristics that place them at the border between the more evolutionarily primitive innate immune system that permits a rapid beneficial response to a variety of foreign agents and the adaptive immune system where B and T cells coordinate a slower but highly antigen specific immune response leading to long lasting memory against subsequent challenges by the same antigen Gamma delta T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and can develop a memory phenotype However the various subsets may also be considered part of the innate immunity 4 in which a specific TCR can function as a pattern recognition receptor 5 For example according to this paradigm large numbers of human Vg9 Vd2 T cells respond within hours to common molecules produced by microbes and highly restricted intraepithelial Vd1 T cells will respond to stressed epithelial cells bearing sentinels of danger Recent work has shown that human Vg9 Vd2 T cells are also capable of phagocytosis a function previously exclusive to innate myeloid lineage cells such as neutrophils monocytes and dendritic cells 6 This provides further evidence that the biology of gamma delta T cells spans both innate and adaptive immune responses Gamma delta T cells in murine thermogenesis EditRecently it was believed that gd17 T cells were only able to produce IL 17 in acute infections It was recently discovered that gd17 T cells can produce IL 17 even when the immune response is not induced These cells are likely to be generated from fetal gd thymocytes and as they egress from the thymus they will progress to non lymphoid tissues such as lungs peritoneal cavity dermis tongue and uterus 7 The gd17 T that will accumulate in the adipose tissue dermis will not only controls the homeostasis of regulatory T cells but also an adaptive thermogenesis therefore they are able to control the maintenance of core body temperature 8 Using aging mice as a model the molecular and cellular mechanisms that act under thermoneutrality circumstances steady state or after cold exposure has been recently acknowledged When the mice is on a steady state IL 17 produced by the gd17 T cells will stimulate stromal cells expressing the IL 17 receptor to produce IL 33 in vivo and therefore provide a molecular link to T reg cells expressing the IL 33 receptor ST2 in the adipose tissue so ST2 Treg cells will accumulate and this will lead to the maintenance of the tissue homeostasis This recent finding explains the mechanism of why the number of T reg cells continuously increases during aging On the other hand it has been shown that after exposing the mice to cold the production of TNF and IL 17 will act on the adipocytes uncoupling the protein UCP1 which is required for inducing a UCP1 dependent thermogenic program 9 Gamma delta T cells in autoimmunity EditAutoimmune disease results from abnormal response of immune system Production of autoantibodies or autoreactive T cells is present during such disease The role of gd T cell in autoimmune disease is to help B cells to produce autoantibodies through proinflammatory cytokines IL 17A is important for development and progression of autoimmune diseases Main sources are Th17 CD4 ab T cells but gd T cell subset plays role in autoimmune pathogenesis and regulation too because they contribute to production of IL 17A and other chemokines They also interact with other innate and adaptive immune cells and modulate their functions gd T cell enhance or suppress inflammation depending on the site and stage of disease They rise from periphery and can be accumulated in inflamed tissue These T cells can become active without TCR ligand they can induce inflammation in autoimmune diseases very fast 10 gd T cells have clinical association with many autoimmune diseases Idiopathic bowel diseases IBD Edit gd T cells are a major T cell subset of intraepithelial lymphocytes IEL present in the epithelial layer of mucosa They regulate immunosuppressive functions of IELs and play role in development of tolerance These so called protective gd T cells promote tissue repair and cell healing Pathogens and other inflammation stimuli cause production of retinoic acid by dendritic cells it induces gd T cells to produce IL 22 This cytokine is responsible for cell mediated production of antimicrobial peptides and tissue repair On the other hand pathogenic gd T cells produce IL 17 This cytokine induces Th17 cells differentiation and dendritic cell mediated production of IL 12 and IL 23 promotes differentiation of Th17 cells to Th1 cells which produce IFN g Matrix metalloproteinases and NO present in inflamed tissue damage and degrade basal membrane leading to development of IBD 11 Type 1 diabetes T1D Edit T1D is an autoimmune disease where b cells of the pancreas which produce insulin are damaged by autoreactive T cells There is infiltration of both innate and adaptive immune cells in pancreas Studies on mice showed that gd T cells play a role in T1D pathogenesis They infiltrate islets and may even co operate with ab T cells to induce T1D 12 Rheumatoid arthritis RA Edit RA is a chronic autoimmune disease caused by accumulation of self reactive T cells which are induced by inflammation in synovial fluid and joints RA patients have higher numbers of gd T cells producing IL 17 It leads to production of inflammatory cytokines by neutrophils macrophages and fibroblasts and RANKL by osteoblasts RANKL causes conversion of precursors into osteoclasts Matrix metalloproteinases and cathepsins induced by inflammatory cytokines together with RANKL cause bone and cartilage erosion which leads to RA development 11 Multiple sclerosis MS Edit gd T cells are involved in development of this autoimmune disease They are cytotoxic against oligodendrocytes cells that participate in the myelinization of axons Patients have increased numbers of gd T cells in brain and cerebrospinal fluid and these cells accumulate in demyelinated areas of CNS and make plaques In the mice models different subsets of gd T cells were identified The most abundant were the ones producing IL 17 IL 17 induces Th17 cells and Th17 response 10 Psoriasis Edit Psoriasis is one of the autoimmune diseases in which the gd T cells together with Th1 and Th17 play an essential role in the disease development In response to IL 23 the adipose gamma T cells will produce IL 17 and this interleukin promotes development and progression of psoriasis 13 Also it has been proven that Vg9Vd2 T cells in patients suffering from Psoriasis participate in the development of the disease 14 The number of Vg9Vd2 T cells increase in the skin lesions of psoriasis patients but decreased in the blood This finding indicates redistribution of Vg9Vd2 T cells from the blood to the skin compartment in psoriasis The psoriasis severity is associated with lower level of g9Vd2 T cells in the circulation therefore a successful anti psoriatic therapy leads to increase of peripheral Vg9Vd2 T cells The major outcome is that the measurement of these cells in blood and skin lesions can be used as a marker in order to follow up the psoriasis progression Gamma delta T cells and cancer EditNon MHC restricted recognition of antigens and high cytokine secretion of gd T cells suggest that these cells would be effective in cancer immunotherapy Trials in numerous cancers renal carcinoma leukemia lung cancer showed that they are tolerated and safe but on the other hand there are reports saying that gd T cells cause cancer development 15 for example through production of IL 17 in tumor microenvironment which promotes angiogenesis and cell growth 16 or because their ability to increase numbers of myeloid derived suppressor cells 17 Therefore the effectiveness of immunotherapy based on gd T cells is limited gd T cells can be divided into two groups effector and regulatory gd T cells Effector functions of gd T cells Edit After infiltrating tumor as a response to chemokines produced by monocytes and macrophages gd T cells interact with stress induced molecules on tumor cells and secrete cytotoxic molecules inflammatory cytokines and activate adaptive immunity cells They can also lyse tumor cells by antibody dependent cellular cytotoxicity ADCC through binding Fc region of IgG deposited on tumor cells gd T cells secrete IFN g and IL 17 which leads to higher expression of MHC I positive regulation of cytotoxic T lymphocytes and induction of anti tumor response gd T cells also interact with DCs and develop Th1 response Regulatory functions of gd T cells Edit Besides effector functions gd T cells have regulatory and suppressive role in the tumor microenvironment through expression of transcription factors FoxP3 Helios and CD86 CTLA 4 interaction between APCs and gd T cells They also impair effector immune cells DC NK iNKT CD8 T cells through IL 4 IL 10 and TGF b Also IL 17 secreted by gd T cells has pro tumorogenic role enhanced angiogenesis recruitment of macrophages expansion and polarization of neutrophils and their suppression of CD8 T cells 18 Gene families in different species EditLaboratory mice Mus musculus Edit Mouse Vg chains Edit This table summarizes the nomenclature of mouse Vg chains and indicates monoclonal antibodies often used to identify these chains This system has been best described in strain C57BL 6 and might not apply well to other strains There are two systems of nomenclature in use Heilig Garman and many writers do not indicate which system they use For example the IMGT International Immunogenetics Information System uses the Heilig notation but does not indicate this fact on its website citation needed This table refers to variable chain Vg gene segments and to monoclonal antibodies that detect the corresponding Vg protein chains Note that Adrian Hayday s proposed nomenclature is not widely used citation needed leaving considerable confusion in the literature One advantage and weakness of the Hayday nomenclature is that it is based on the gene order in the B6 genome but this might not apply to other strains Heilig and Tonegawa s system 19 Garman s system 20 Hayday s system 21 antibodies commentsVg5 Vg3 GV1S1 536 17D1 specific for Vg5 Heilig Vd1 clonotype Skin Jg1Cg1Vg6 Vg4 GV2S1 17D1 can detect Vg6Vd1 when pretreated with GL3 antibodies reproductive mucosa Jg1Cg1Vg4 Vg2 GV3S1 UC310A6 lung Jg1Cg1Vg7 Vg5 GV4S1 F2 67 Pereira most common form in intestinal IEL orthologous to human Vg1 Jg1Cg1Vg1 Vg1 1 GV5S1 2 11 Pereira 1995 peripheral lymphoid tissues Jg4Cg4Vg2 Vg1 2 GV5S2 Jg1Cg1Vg3 Vg1 3 GV5S3 Jg3 pseudoCg3 Mouse Vgamma locus for C57BL 6 genome drawn to scale Chromosome 13 1 927 to 1 440 Megabp Heilig notation Human forms Edit Human Vd2 T cells Edit Vg9 Vd2 T cells are unique to humans and primates and represent a minor and unconventional constituent of the leukocyte population in peripheral blood 0 5 5 yet they are assumed to play an early and essential role in sensing danger by invading pathogens as they expand dramatically in many acute infections and may exceed all other lymphocytes within a few days e g in tuberculosis salmonellosis ehrlichiosis brucellosis tularemia listeriosis toxoplasmosis and malaria Of note all Vg9 Vd2 T cells recognize the same small microbial compound E 4 hydroxy 3 methyl but 2 enyl pyrophosphate HMB PP a natural intermediate of the non mevalonate pathway of isopentenyl pyrophosphate IPP biosynthesis 22 HMB PP is an essential metabolite in most pathogenic bacteria including Mycobacterium tuberculosis and malaria parasites but is absent from the human host Bacterial species that lack the non mevalonate pathway and synthesize IPP via the classical mevalonate pathway instead such as Streptococcus Staphylococcus and Borrelia are unable to produce HMB PP and do not specifically activate Vg9 Vd2 T cells IPP itself is structurally closely related to HMB PP and ubiquitously present in all living cells including human cells yet its potency in vitro is reduced 10 000 fold whether IPP represents a physiological danger signal of stressed or transformed cells is still unclear Of pharmacological interest and with bioactivities comparable to that of IPP are synthetic aminobisphosphonates such as zoledronate Zometa or pamidronate Aredia that are widely used to treat osteoporosis and bone metastases and incidentally act as Vg9 Vd2 T cell receptor agonists However increasing evidence suggests that these aminobisphosphonate antigens are not recognised directly by Vg9 Vd2 T cells and in fact act indirectly via their effects on the mevalonate biosynthetic pathway leading to an accumulation of IPP 23 Finally certain alkylated amines have been described to activate Vg9 Vd2 T cells in vitro however only at millimolar concentrations i e with potencies 106 108 fold lower than those of HMB PP thereby raising questions about their physiological relevance It is still not clear whether these non peptidic antigens bind directly to the Vg9 Vd2 TCR or if a presenting element exists There is evidence for a requirement for a species specific cell cell contact However none of the known antigen presenting molecules like MHC class I and II or CD1 are required for gd T cell activation suggesting the existence of a novel presenting element Strong support for a direct recognition of non peptide antigens by the Vg9 Vd2 TCR comes from studies which demonstrated that a transfected Vg9 Vd2 TCR can confer responsiveness onto a hitherto unresponsive cell furthermore antibodies to the gd TCR block recognition Thus the presence of a functional Vg9 Vd2 TCR appears mandatory for a response to non peptidic antigens although the basis for the huge differences in bioactivity between closely related molecules like HMB PP and IPP cannot be explained by conventional epitope presentation recognition models These Vg9Vd2 T cells can also behave like professional antigen presenting cells APC It seems that human Vg9Vd2 T cells are characterized by a specific inflammatory migration program including multiple receptors for inflammatory chemokines CXCR3 CCR1 CCR2 and CCR5 It means that the stimulation with IPP or HMB PP induces migration to the lymphatic tissues specifically to the T cell area of lymph nodes So the stimulation of Vg9Vd2 T cells with phosphoantigens results in expression of multiple markers which are associated with APC like MHC I and II molecules co stimulatory molecules CD80 CD86 and adhesion receptors CD11a CD18 CD54 Thus activated Vg9Vd2 T cells behave like APCs gd T APC and present antigens to ab T cells This leads to turn of naive CD4 and CD8 ab T cells into effector cells The differentiation induced by gd T APC most often led to T helper cell response in the most of cases to pro inflammatory Th1 response with subsequent production of IFN g and TNF a But in the case of a low gd T APC CD4 ratio it leads to differentiation of some naive ab T cells into Th2 IL 4 or Th0 IL 4 plus IFN g cells Human Vg9Vd2 T cells are also cells with excellent antigen cross presentation activity a process describing the uptake of exogenous antigen and its routing to the MHC I pathway for induction CD8 cytotoxic T cells Thus activated cytotoxic T cells can effectively kill infected or tumor cells This fact can be used in the immunotherapy of cancer and infectious diseases 24 Human non Vd2 T cells Edit The extensive structural diversity of Vd1 and Vd3 TCRs and the existence of Vd1 clones reactive against MHC MHC like or non MHC molecules suggest recognition of a highly diverse and heterogeneous set of antigens by non Vd2 cells although cognate interactions between non Vd2 TCRs and any of these antigens have not been shown yet MHC class I chain related gene A MICA has also been proposed as an important tumor antigen recognized by Vd1 T cells However the very low affinity of MICA Vd1 TCR interactions estimated by surface plasmon resonance analyses raises doubts about the functional relevance of MICA or MHC class I chain related gene B MICB recognition by Vd1 TCRs Non Vd2 gd T cells are expanded in various infectious contexts involving intracellular bacteria Mycobacteria and Listeria as well as extracellular bacteria such as Borrelia burgdorferi and viruses HIV cytomegalovirus In most instances the stimuli that trigger Vd1 expansion are not derived from pathogens but instead correspond to endogenous gene products presumably upregulated on infection The antigens recognized by non Vd2 T cells expanded in the above infectious contexts have not been characterized but the fact that Vd1 T cell responses are not blocked by monoclonal antibody directed against known classical or non classical MHC molecules suggests recognition of a new class of conserved stress induced antigens A recent study of primary cytomegalovirus infection in infants found increased Vd1 T cells that also expressed the typically NK cell associated markers NKG2C and CD57 25 A recent study has identified a specific subset of gut resident Vd1 IELs intraepithelial lymphocytes which express high levels of a natural cytotoxic receptor NCR which is NKp46 These receptors are expressed almost exclusively by natural killer NK cells and play a central role in triggering their activation but it has been described that gd T cells can express these receptors 26 These cells are named NKp46 Vd1 IELs The major outcome of this study is the clinical relevance of this cells which can be used a prognostic marker in the colorectal cancer CRC in order to follow up its progression Lower frequencies of NKp46 Vd1 IELs in healthy intestinal tissues surrounding the tumor mass associate with a higher tumor progression and metastasis It is acknowledged that this subset can control the metastasis so the higher levels of this population the less probabilities for the tumor to progress and proliferate to other tissues 27 See also EditNaive T cells Memory T cells Helper T cells Cytotoxic T cells Natural killer T cells Innate immune system Adaptive immune system Regulatory T cellsReferences Edit a b Holtmeier W Kabelitz 2005 Gd T Cells Link Innate and Adaptive Immune Responses Mechanisms of Epithelial Defense Chemical Immunology and Allergy 86 pp 151 183 doi 10 1159 000086659 ISBN 3 8055 7862 8 PMID 15976493 Bergstresser PR Sullivan S Streilein JW Tigelaar RE July 1985 Origin and function of Thy 1 dendritic epidermal cells in mice The Journal of Investigative Dermatology 85 1 Suppl 85s 90s doi 10 1111 1523 1747 ep12275516 PMID 2409184 Jameson J Havran WL February 2007 Skin gammadelta T cell functions in homeostasis and wound healing Immunological Reviews 215 114 122 doi 10 1111 j 1600 065X 2006 00483 x PMID 17291283 S2CID 83853368 Born WK Reardon CL O Brien RL February 2006 The function of gammadelta T cells in innate immunity Current Opinion in Immunology 18 1 31 38 doi 10 1016 j coi 2005 11 007 PMID 16337364 Morita CT Mariuzza RA Brenner MB 2000 Antigen recognition by human gamma delta T cells pattern recognition by the adaptive immune system Springer Seminars in Immunopathology 22 3 191 217 doi 10 1007 s002810000042 PMID 11116953 S2CID 8146031 Wu Y Wu W Wong WM Ward E Thrasher AJ Goldblatt D et al November 2009 Human gamma delta T cells a lymphoid lineage cell capable of professional phagocytosis Journal of Immunology 183 9 5622 5629 doi 10 4049 jimmunol 0901772 PMID 19843947 Chien YH Zeng X Prinz I April 2013 The natural and the inducible interleukin IL 17 producing gd T cells Trends in Immunology 34 4 151 154 doi 10 1016 j it 2012 11 004 PMC 3622789 PMID 23266231 Kohlgruber AC Gal Oz ST LaMarche NM Shimazaki M Duquette D Koay HF et al May 2018 gd T cells producing interleukin 17A regulate adipose regulatory T cell homeostasis and thermogenesis Nature Immunology 19 5 464 474 doi 10 1038 s41590 018 0094 2 PMC 8299914 PMID 29670241 S2CID 4986319 Papotto PH Silva Santos B May 2018 Got my gd17 T cells to keep me warm Nature Immunology 19 5 427 429 doi 10 1038 s41590 018 0090 6 hdl 10451 49126 PMID 29670236 S2CID 4937603 a b Shiromizu CM Jancic CC 16 October 2018 gd T Lymphocytes An Effector Cell in Autoimmunity and Infection Frontiers in Immunology 9 2389 doi 10 3389 fimmu 2018 02389 PMC 6198062 PMID 30386339 a b Paul S Lal G February 2015 Role of gamma delta gd T cells in autoimmunity Journal of Leukocyte Biology 97 2 259 271 doi 10 1189 jlb 3RU0914 443R PMID 25502468 Markle JG Mortin Toth S Wong AS Geng L Hayday A Danska JS June 2013 gd T cells are essential effectors of type 1 diabetes in the nonobese diabetic mouse model Journal of Immunology 190 11 5392 5401 doi 10 4049 jimmunol 1203502 PMC 3836168 PMID 23626013 Cruz MS Diamond A Russell A Jameson JM 6 June 2018 Human ab and gd T Cells in Skin Immunity and Disease Frontiers in Immunology 9 1304 doi 10 3389 fimmu 2018 01304 PMC 5997830 PMID 29928283 Laggner U Di Meglio P Perera GK Hundhausen C Lacy KE Ali N et al September 2011 Identification of a novel proinflammatory human skin homing Vg9Vd2 T cell subset with a potential role in psoriasis Journal of Immunology 187 5 2783 2793 doi 10 4049 jimmunol 1100804 PMC 3187621 PMID 21813772 Zhao Y Niu C Cui J January 2018 Gamma delta gd T cells friend or foe in cancer development Journal of Translational Medicine 16 1 3 doi 10 1186 s12967 017 1378 2 PMC 5761189 PMID 29316940 Silva Santos B July 2010 Promoting angiogenesis within the tumor microenvironment the secret life of murine lymphoid IL 17 producing gammadelta T cells European Journal of Immunology 40 7 1873 1876 doi 10 1002 eji 201040707 PMID 20549671 S2CID 7160235 Qu P Wang LZ Lin PC September 2016 Expansion and functions of myeloid derived suppressor cells in the tumor microenvironment Cancer Letters 380 1 253 256 doi 10 1016 j canlet 2015 10 022 PMC 7477794 PMID 26519756 Paul S Lal G September 2016 Regulatory and effector functions of gamma delta gd T cells and their therapeutic potential in adoptive cellular therapy for cancer International Journal of Cancer 139 5 976 985 doi 10 1002 ijc 30109 PMID 27012367 S2CID 33681064 Heilig JS Tonegawa S 1986 Diversity of murine gamma genes and expression in fetal and adult T lymphocytes Nature 322 6082 836 840 Bibcode 1986Natur 322 836H doi 10 1038 322836a0 PMID 2943999 S2CID 4338771 Garman RD Doherty PJ Raulet DH June 1986 Diversity rearrangement and expression of murine T cell gamma genes Cell 45 5 733 742 doi 10 1016 0092 8674 86 90787 7 PMID 3486721 S2CID 46363401 Hayday AC 2000 gamma delta cells a right time and a right place for a conserved third way of protection Annual Review of Immunology 18 975 1026 doi 10 1146 annurev immunol 18 1 975 PMID 10837080 Eberl M Hintz M Reichenberg A Kollas AK Wiesner J Jomaa H June 2003 Microbial isoprenoid biosynthesis and human gammadelta T cell activation FEBS Letters 544 1 3 4 10 doi 10 1016 S0014 5793 03 00483 6 PMID 12782281 S2CID 9930822 Hewitt RE Lissina A Green AE Slay ES Price DA Sewell AK January 2005 The bisphosphonate acute phase response rapid and copious production of proinflammatory cytokines by peripheral blood gd T cells in response to aminobisphosphonates is inhibited by statins Clinical and Experimental Immunology 139 1 101 111 doi 10 1111 j 1365 2249 2005 02665 x PMC 1809263 PMID 15606619 Moser B Eberl M July 2011 gd T APCs a novel tool for immunotherapy Cellular and Molecular Life Sciences 68 14 2443 2452 doi 10 1007 s00018 011 0706 6 PMID 21573785 S2CID 22604758 Tuengel J Ranchal S Maslova A Aulakh G Papadopoulou M Drissler S et al Oct 2021 Characterization of Adaptive gd T Cells in Ugandan Infants During Primary Cytomegalovirus Infection Viruses 13 10 1987 doi 10 3390 v13101987 PMC 8537190 PMID 34696417 von Lilienfeld Toal M Nattermann J Feldmann G Sievers E Frank S Strehl J Schmidt Wolf IG June 2006 Activated gammadelta T cells express the natural cytotoxicity receptor natural killer p 44 and show cytotoxic activity against myeloma cells Clinical and Experimental Immunology 144 3 528 533 doi 10 1111 j 1365 2249 2006 03078 x PMC 1941970 PMID 16734623 Mikulak J Oriolo F Bruni E Roberto A Colombo FS Villa A et al December 2019 NKp46 expressing human gut resident intraepithelial Vd1 T cell subpopulation exhibits high antitumor activity against colorectal cancer JCI Insight 4 24 doi 10 1172 jci insight 125884 PMC 6975269 PMID 31689241 Further reading EditHayday AC April 2000 gamma delta cells a right time and a right place for a conserved third way of protection Annual Review of Immunology 18 1 975 1026 doi 10 1146 annurev immunol 18 1 975 PMID 10837080 Girardi M January 2006 Immunosurveillance and immunoregulation by gammadelta T cells The Journal of Investigative Dermatology 126 1 25 31 doi 10 1038 sj jid 5700003 PMID 16417214 Thedrez A Sabourin C Gertner J Devilder MC Allain Maillet S Fournie JJ et al February 2007 Self non self discrimination by human gammadelta T cells simple solutions for a complex issue Immunological Reviews 215 1 123 135 doi 10 1111 j 1600 065X 2006 00468 x PMID 17291284 S2CID 86017229 External links Editgammadelta T cell Forum Retrieved from https en wikipedia org w 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