IntroductionIL-17 is a cytokine that induces mobilization and activation of neutrophils and triggers the production of proinflammatory cytokines and chemokines by a broad range of cellular targets. 1 It is predominantly produced by ␣␤ T cells, but also by natural killer (NK) T cells, 2 ␥␦ T cells, 3 and other non-T cells, such as macrophages and neutrophils. 4,5 Differentiation of CD4 T cells producing IL-17 (Th17) is initiated in naive Th cells by antigen-specific stimulation in the presence of the polarizing cytokines IL-1␤, TGF-␤, and IL-6 (and autocrine IL-21), which induce the expression of IL-23 receptor (IL-23R), the chemokine receptor CCR6, and the Th17-specifying transcription factor ROR␥t, which is necessary and sufficient for induction of IL-17. 1,6 In mice, ␥␦ T cells represent an innate source of IL-17 and precede the development of the adaptive Th17-cell response. For instance, during Mycobacterium tuberculosis and Escherichia coli infection, ␥␦ T cells are the primary source of 8 and their depletion causes decreased IL-17 production and neutrophil infiltration into the peritoneal cavity. 8 In Listeria monocytogenes infection, ␥␦ T cells producing IL-17 enhance the antibacterial activity of nonphagocytic cells, which correlates with the induction of ␤-defensin gene expression. 9 These results indicate a novel IL-17-dependent protective mechanism of ␥␦ T cells that acts against intracellular bacterial infections in the mouse. The authors of several recent studies have provided data on the differentiation, phenotype, and functions of murine ␥␦ T cells producing IL-17 [10][11][12][13][14][15] and have demonstrated that signals through the ␥␦ TCR are not required for IL-17 production; instead, this process seems to be controlled by innate cytokines produced by accessory cells such as macrophages or dendritic cells (DCs). 11,15,16 Conversely, few groups have investigated IL-17 production by human ␥␦ T cells.Most human peripheral blood ␥␦ T cells express a TCR consisting of the V␥9 and the V␦2 chains (here and thereafter referred to as V␥9V␦2 T cells) and recognize nonpeptidic phosphorylated metabolites of isoprenoid biosynthesis produced by microorganisms and stressed cells. [17][18][19] On activation, V␥9V␦2 T cells promote DC maturation, 20 B-cell activation, 21 and polarize adaptive immunity toward a Th1 immune response. 10 Such a broad plasticity emphasizes the capacity of V␥9V␦2 T cells to influence the nature of immune response to different challenges. Human ␥␦ T cells producing IL-17 have been detected in the peripheral blood of patients with tuberculosis 22 or HIV infection, 23 but in neither of these studies did the authors characterize the IL-17-and IL-22-producing ␥␦ T cells or examine the cytokine requirements for IL-17 production.The authors of a very recent study have demonstrated that IL-17A-and IL-22-producing V␥9V␦2 T cells exist at low but significant frequencies in human and nonhuman primates, 24 and have suggested that V␥9V␦2 T cells can be polarized into Th17 (producing only IL-17),...

SummaryThe potent anti-tumour activities of gd T cells have prompted the development of protocols in which gd-agonists are administered to cancer patients. Encouraging results from small Phase I trials have fuelled efforts to characterize more clearly the application of this approach to unmet clinical needs such as metastatic carcinoma. To examine this approach in breast cancer, a Phase I trial was conducted in which zoledronate, a Vg9Vd2 T cell agonist, plus low-dose interleukin (IL)-2 were administered to 10 therapeutically terminal, advanced metastatic breast cancer patients. Treatment was well tolerated and promoted the effector maturation of Vg9Vd2 T cells in all patients. However, a statistically significant correlation of clinical outcome with peripheral Vg9Vd2 T cell numbers emerged, as seven patients who failed to sustain Vg9Vd2 T cells showed progressive clinical deterioration, while three patients who sustained robust peripheral Vg9Vd2 cell populations showed declining CA15-3 levels and displayed one instance of partial remission and two of stable disease, respectively. In the context of an earlier trial in prostate cancer, these data emphasize the strong linkage of Vg9Vd2 T cell status to reduced carcinoma progression, and suggest that zoledronate plus low-dose IL-2 offers a novel, safe and feasible approach to enhance this in a subset of treatmentrefractory patients with advanced breast cancer.

Colon cancer comprises a small population of cancer stem cells (CSC) that is responsible for tumor maintenance and resistant to cancer therapies, possibly allowing for tumor recapitulation once treatment stops. We previously demonstrated that such chemoresistance is mediated by autocrine production of IL-4 through the up-regulation of antiapoptotic proteins. Several innate and adaptive immune effector cells allow for the recognition and destruction of cancer precursors before they constitute the tumor mass. However, cellular immune-based therapies have not been experimented yet in the population of CSCs. Here, we show that the bisphosphonate zoledronate sensitizes colon CSCs to Vγ9Vδ2 T cell cytotoxicity. Proliferation and production of cytokines (TNF-α and IFN-γ) and cytotoxic and apoptotic molecules (TRAIL and granzymes) were also induced after exposure of Vγ9Vδ2 T cells to sensitized targets. Vγ9Vδ2 T cell cytotoxicity was mediated by the granule exocytosis pathway and was highly dependent on isoprenoid production by of tumor cells. Moreover, CSCs recognition and killing was mainly TCR mediated, whereas NKG2D played a role only when tumor targets expressed several NKG2D ligands. We conclude that intentional activation of Vγ9Vδ2 T cells by zoledronate may substantially increase antitumor activities and represent a novel strategy for colon cancer immunotherapy.

Vγ9Vδ2 T lymphocytes recognize nonpeptidic Ags and mount effector functions in cellular immune responses against microorganisms and tumors, but little is known about their role in Ab-mediated immune responses. We show here that expression of CXCR5 identifies a unique subset of Vγ9Vδ2 T cells which express the costimulatory molecules ICOS and CD40L, secrete IL-2, IL-4, and IL-10 and help B cells for Ab production. These properties portray CXCR5+Vγ9Vδ2 T cells as a distinct memory T cell subset with B cell helper function.

γδ T cells usually infiltrate many different types of cancer, but it is unclear whether they inhibit or promote tumor progression. Moreover, properties of tumor-infiltrating γδ T cells and those in the corresponding normal tissue remain largely unknown. Here we have studied features of γδ T cells in colorectal cancer, normal colon tissue and peripheral blood, and correlated their levels with clinicopathologic hallmarks. Flow cytometry and transcriptome analyses showed that the tumor comprised a highly variable rate of TILs (5-90%) and 4% γδ T cells on average, with the majority expressing Vδ1. Most Vδ1 and Vδ2 T cells showed a predominant effector memory phenotype and had reduced production of IFN- γ which was likely due to yet unidentified inhibitory molecules present in cancer stem cell secretome. Transcriptome analyses revealed that patients containing abundant γδ T cells had significantly longer 5-year disease free survival rate, suggesting their efficacy in controlling tumor at very early stage.