## 1 Introduction
### Human Adult \(\gamma\delta\) T Cells Subsets  
Human \(\gamma\delta\) T cells are divided into two main subsets based on their TCR usage of the V\(\delta\)1 chain or V\(\delta\)2 chain. Most of \(\gamma\delta\) T cells in human blood use the V\(\delta\)2 chain [16] which is typically paired with the V\(\gamma\)9 chain [17]. Once activated, V\(\delta\)2 cells are a source of pro-inflammatory cytokines such as IFN-\(\gamma\) and TNF-\(\alpha\) and typically recognize pyrophosphate antigens produced by bacteria [16]. V\(\gamma\)9V\(\delta\)2 T cells account for 50-95% of the peripheral \(\gamma\delta\) T cells within the 1-5% \(\gamma\delta\) T cells in circulation. The V\(\gamma\)9V\(\delta\)2 T cells are specially adapted for tumor immunity through potent and broad tumor cytotoxicity, MHC-independency, relative resilience to the suppressive role of programmed cell death-1 (PD-1), low IL-17A production, and activation of NK cells cytotoxicity [18]. V\(\delta\)2 \(\gamma\delta\) T cells have a semi-invariant TCR and mainly behave in an innate-like manner. In adult humans, the \(\gamma\) repertoire of V\(\gamma\)9V\(\delta\)2 T cells is public, whereas the \(\delta\) repertoire is private [19; 20; 21]. V\(\delta\)1 \(\gamma\delta\) T cells represent the predominant T cell subset in solid tissues and the second most frequent subset in peripheral blood (1-3% of lymphocytes) next to V\(\gamma\)9V\(\delta\)2 T cells. V\(\delta\)1 T cells mainly reside in mucosal epithelial tissues, comprising approximately 40% of all intra-epithelial lymphocytes in the large intestine, and display potent anti-tumor activity. The V\(\delta\)1 TCR repertoire in adult humans is often private, primarily consisting of a few clones, sharing adaptive immunity features [22; 23; 24]. V\(\delta\)1 cells via their NKG2D receptors recognize MHC class I related polymorphic molecules such as MICA/MICB [16] and UL16-binding protein (ULBP) which are induced upon stress, damage, or transformation of cells. By engaging NKG2D receptor, MICA/B and ULBP act as a 'kill me' signal for the cytotoxic T cells [25] (Figure 1). Figure 1: Mechanisms of \(\gamma\)\(\delta\) T cells activation. Bisphosphonates (BP) and nitrogenous-BP (N-BP) block the farnesyl pyrophosphate synthase (FPPS) enzyme in isoprenoid biosynthesis pathway in target cell or antigen presenting cells (APC) which leads to the accumulation of isopentenyl pyrophosphate (IPP) and its metabolites. IPP and geranyl pyrophosphate (GPP) react with cytoplasmic tail of butylophilin-3 subfamily molecules (e.g., BTN3A1) and stir a change which is detectable by \(\gamma\)\(\delta\) TCR. IPP metabolites can also be converted into an ATP analog (ApppI). ApppI can be presented at the cell surface and be recognized by the \(\gamma\)\(\delta\) TCR; however, the molecular mechanism of this process is not yet clear. Some of the known ligands for V81 and V82 T cells are shown here. Cell stress and bacterial pathogens induce expression of MHC class I chain-related protein A and protein B (MICA/MICB) molecules which react with NKG2D on V81. MICA also binds to NKG2D on V9V82 T cells. Several members of BTN family such as BTN3A1, BTN3A2, and BTN2A can bind to V82 TCR and activate V82 T cells. This activation is often via mechanisms involving multimization of BTN molecules and exerting a synergistic effect. Moreover, UL16-binding protein (ULBP) which is a ligand for NKG2D receptor, as well as involvement of CD28 and 4-1 BB receptors with their ligands provides additional costimulatory signals for \(\gamma\)\(\delta\) T cells. Most studies on human \(\gamma\delta\) T cells have focused on the V52 and V81 subsets, although there are other subsets of \(\gamma\delta\) T cells with different distribution in various tissues. Of these, the V53 cells represent a minor subset found in blood (\(\approx\)0.2% of lymphocytes), liver, and gut, that is often described as V81-V82-V. V83 T cells expand in presence of CMV and have been shown to induce dendritic cells (DC) and B cell maturation [26].