Gamma delta T cells (γδ T cells) are T cells that have a γδ 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, 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. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).
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), 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).
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' only address facets of their complex behavior. In fact, γδ 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, 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 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 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.
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 have recently been acknowledged.
When mice are in 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 tissue homeostasis. This recent finding explains the mechanism by which the number of T reg cells continuously increases during aging. On the other hand, it has been shown that, after exposing 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.
Autoimmunity 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 cells 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.
Inflammatory 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 with 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.
Cancer Non-MHC restricted recognition of antigens and high cytokine secretion of γδ T cells suggest that these cells can be effective in cancer immunotherapy. Trials in numerous cancers (renal carcinoma, leukemia, lung cancer) showed that they are tolerated and safe, but some studies report that γδ T cells cause cancer development for example through production of IL-17 in the 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. Their invariant nature implies that immunotherapies that rely on them would not require customization for individual patients.
γδ T cells can be divided into effector and regulatory cells:
Effector functions After infiltrating a 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 γδ T cells perform a regulatory and suppressive role in the TME 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).
Gene families in different species Laboratory mice (Mus musculus) Mouse Vγ chains