Γδ T cells

γδ T cells represent a small subset of T cells that possess a distinct T cell receptor (TCR) on their surface. A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- TCR chains. In contrast, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is usually much less common than αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

The antigenic molecules that activate γδ T cells are still largely unknown. However, γδ T cells are peculiar in that they do not seem to require antigen processing and 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.

There also exists a γδ T cell sub-population within the epidermal compartment of the skin. Named Dendritic Epidermal γδ T cells (DETC), these cells arise during fetal development and express an invariant and canonical Vγ3 Vδ1 T cell receptor (TCR).

γδ T cells in innate and adaptive immunity
The conditions that lead to responses of γδ T cells are not fully understood, and current concepts of γδ T cells 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. Mature γδ T cells are divided into functionally distinct subsets that obey their own (mostly unknown) rules and that have countless direct and indirect effects on healthy tissues and immune cells, on 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.


 * On one hand, γδ T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and will develop a memory phenotype.


 * However, the various subsets may also be considered part of the innate immunity where a restricted TCR may be used as a pattern recognition receptor. For example, according to this paradigm, large numbers of 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.

Clearly, the complexity of γδ T cell biology spans definitions of both innate and adaptive immune responses.

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 (i.e. also in 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. Finally, certain alkylated amines have been described to activate Vγ9/Vδ2 T cells in vitro, however only at millimolar concentrations, i.e. with potencies 106-108fold lower than those of HMB-PP, thereby questioning 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.

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.