V9V2-T cells are considered as potent effector cells for tumor immunotherapy through directly killing tumor cells and indirectly regulating additional innate and adaptive immune cells to establish antitumoral immunity. can distinguish between tumorous and normal cells using T cell receptor (TCR) and additional innate receptors to sense isopentenyl pyrophosphate (IPP) levels and stress signals (such as MICA/B, ULBP4, and MSH2) displayed on target cells. Most importantly, TCR is the predominant element that can result in cell activation without any contribution of additional co-stimulators, such as NKG2D. Following TCR-dependent activation, V9V2-T Pyr6 cells identify and destroy tumor cells by liberating effector molecules, such as granzymes and perforin, and Th-1 cytokines, inducing target cell apoptosis Fas/FasL, TNF-related apoptosis-inducing ligand (TRAIL) and TNF- pathways, and antibody-dependent cell-mediated cytotoxicity through CD16 expression. The activation threshold is definitely finely regulated by inhibitory receptors, such as NKG2A/CD94. Moreover, adhesion patterns, such as lymphocyte function-associated antigen 1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1), will also be involved in regulating the antitumoral activity of V9V2-T cells. The chemokine receptors, including CCR5, control the ability of V9V2-T cell to migrate to the tumor site. The survival and proliferation of V9V2-T cells are mostly modulated by different cytokines, such as IL-2 and IL-15. Peptide Ligands (1) Self ligands: in addition to non-peptide ligands, V9V2-T cells can also identify some molecules of cellular source, which could be capable of indicating cellular stress or malignant transformation (49, 62). Several self-antigens have been confirmed to bind to V9V2-TCR, including warmth shock protein-60 (HSP 60) (63), U16-binding protein 4 (ULBP-4) (64), human being MutS homolog 2 (hMSH2) (63, 65), and F1-ATP synthase (F1-ATPase) (59, 66). The expressions of these proteins are shown to be upregulated on the surface of different tumor cells and they can promote acknowledgement by V9V2-T cells. It is intriguing that ULBP-4 and Pyr6 hMSH2 can also bind to NKG2D to induce the cytotoxicity of V9V2-T cells against tumor cells through TCR and NKG2D engagement (63C65) (Number ?(Figure11). (2) Non-self ligands: tetanus toxoid (67), Ig light chain (68), and viral proteins, such as glycoprotein I from (69) and staphylococcal enterotoxin A (70), are antigens that were reported to be capable of stimulating V9V2-T cell reactions. Cell Receptor Engagement Besides the V9V2-TCR engagement, some other cellular receptors, especially the NK receptors (NKRs), are involved in the effective triggering of antitumoral reactions of V9V2-T cells (49) (Number ?(Figure1).1). Together with previous studies, we reported that NKG2D can bind to its ligands (71), such as MICA, MICB, and ULBP-1, -2, -3, and -4, which are expressed in different tumors, including leukemia, lymphoma, ovarian, and colon carcinoma (72C74). In particular, the high manifestation level of ULBP1 shows the susceptibility of lymphoma to V9V2-T cell-mediated cytolysis (74). Furthermore, ULBP-4 manifestation is detected within the cell surface of EBV-transformed Pyr6 lymphoid cells lines as well as on colon, ovarian, and liver malignancy cells (64). Another NKR implicated in tumor acknowledgement by V9V2-T cells is the DNAX accessory molecule-1 (DNAM-1) (75, 76). Nectin-like-5 and Nectin-2, ligands of DNAM-1, are indicated on most hepatocellular carcinoma (HCC) cell lines (75). In addition, some V9V2-T cells also communicate NKp44, which can mediate their cytotoxic activity against multiple myeloma (MM) cell lines (77, 78). Much like NK cells, V9V2-T cells also communicate high levels of CD16 (FcR III) upon phosphoantigen activation (79), and thus leading to antibody-dependent cell-mediated cytotoxicity Pyr6 (ADCC) against STMY tumor cells (80C83). -T Cells Act as Effector Cells V9V2-T Cells with Killer Functions Connection of TCR and/or NKG2D with their respective ligands can stimulate the activation of V9V2-T cells. Once triggered, V9V2-T cells secrete IFN- and TNF-, and increase the launch Pyr6 of antitumor effector molecules, such as perforin and granzymes. The DNAM-1 signaling pathway can positively regulate the cytotoxic activity and IFN- secretion of V9V2-T cells against a broad range of tumors. Antibody-dependent cell-mediated cytotoxicity mediated by V9V2-T cells can be triggered the binding of CD16 to antibodies, such as rituximab, trastuzumab, atumumab, and alemtuzumab, coated on the particular tumor cells (80C83). In addition, triggered V9V2-T cells can also induce tumor cell apoptosis TNF-related apoptosis-inducing ligand and Fas/FasL.