Gamma delta T cell

Source: Wikipedia, the free encyclopedia.
(Redirected from
Γδ T cells
)

Gamma delta T cells (γδ T cells) are

mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).[1]

The antigenic molecules that activate γδ T cells are largely unknown. 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. γδ T cells are believed to have a prominent role in lipid antigen recognition. They are of an invariant nature. They may be triggered by alarm signals such as heat shock proteins (HSP).

A γδ-T-cell sub-population exists within the

epidermal compartment of mice skin. 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 Vγ3 Vδ1 T-cell receptor (using Garman nomenclature).[3]

Innate and adaptive immunity

The conditions that lead to responses of γδ 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'

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

Natural Killer T cells, γδ 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.

γδ 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) 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 [6] This provides further evidence that the biology of γδ T cells spans both innate and adaptive immune responses.

Murine thermogenesis

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.[7]

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.[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

UCP1, which is required for inducing a UCP1-dependent thermogenic program.[9]

Autoimmunity

cytokines
.
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.[10]

γδ T cells have clinical association with many autoimmune diseases.

Inflammatory bowel diseases IBD

γδ T cells are a major T cell subset of intraepithelial lymphocytes (IEL) present in the epithelial layer of

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

basal membrane, leading to development of IBD.[11]

Type 1 diabetes T1D

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.[12]

Rheumatoid arthritis RA

RA is a chronic autoimmune disease caused by accumulation of self-reactive T cells, which are induced by inflammation in

cathepsins induced by inflammatory cytokines, together with RANKL, cause bone and cartilage erosion, which leads to RA development.[11]

Multiple sclerosis MS

γδ T cells are involved in development of this autoimmune disease. They are

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.[10]

Psoriasis

Psoriasis is one of the autoimmune diseases in which the γδ T cells together with

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 Vγ9Vδ2 T cells in patients with Psoriasis participate in the development of the disease.[14]
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.

Cancer

Non-MHC restricted recognition of

renal carcinoma, leukemia,[15] lung cancer) showed that they are tolerated and safe, but some studies report that γδ T cells cause cancer development[16] for example through production of IL-17 in the tumor microenvironment, which promotes angiogenesis and cell growth[17] or because their ability to increase numbers of myeloid derived suppressor cells.[18] Therefore, the effectiveness of immunotherapy based on γδ T cells is limited. Their invariant nature implies that immunotherapies that rely on them would not require customization for individual patients.[19]

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

Effector functions

After infiltrating a tumor as a response to

Th1 response
.

Regulatory functions

γδ T cells perform a regulatory and suppressive role in the TME expression of

CD8+ T cells).[21]

Gene families in different species

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[22] 		Garman's system
[23] 		"Hayday's system[24]" 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 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.

HMB-PP
, thereby raising questions about their physiological relevance.

It is still not clear whether these

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 (

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 (
tumor cells. This fact can be used in the immunotherapy of cancer and infectious diseases.[27]

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 (

CD57[28]

A recent study has identified a specific subset of

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.[29]
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.[30]

See also

References

  1. ^
    PMID 15976493
    .
  2. PMID 2409184
    .
  3. S2CID 83853368
    .
  4. PMID 16337364
    .
  5. S2CID 8146031
    .
  6. PMID 19843947
    .
  7. PMID 23266231
    .
  8. S2CID 4986319
    .
  9. S2CID 4937603
    .
  10. ^
    PMID 30386339
    .
  11. ^
    PMID 25502468
    .
  12. PMID 23626013
    .
  13. PMID 29928283
    .
  14. PMID 21813772
    .
  15. ^
    PMID 34630403
    .
  16. PMID 29316940
    .
  17. S2CID 7160235
    .
  18. PMID 26519756
    .
  19. ^ Irving, Michael (2023-11-13). ""Off-the-shelf" cancer immunotherapy inches closer with new mouse study". New Atlas. Retrieved 2023-11-13.
  20. PMID 33506055
    .
  21. S2CID 33681064
    .
  22. S2CID 4338771
    .
  23. S2CID 46363401
    .
  24. PMID 10837080
    .
  25. S2CID 9930822
    .
  26. PMID 15606619
    .
  27. S2CID 22604758
    .
  28. PMID 34696417
    .
  29. PMID 16734623
    .
  30. PMID 31689241
    .

Further reading

Retrieved from "https://en.wikipedia.org/w/index.php?title=Gamma_delta_T_cell&oldid=1189925409"