Differentiation, phenotype, and function of interleukin-17–producing human Vγ9Vδ2 T cells

Abstract

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),...

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

“…7B). IL-17 was completely undetectable, even in gd T cell cultures containing IL-1b, which was previously shown to support differentiation of IL-17-producing Vg9Vd2 T cells (46).…”

“…IL-17 could not be detected in PBMCs or in purified gd T cells, even in the presence of IL-1b and IL-18, which have been implicated in the regulation of IL-17 production in humans and mice (46,53), respectively. The requirements for the differentiation of IL-17-producing human Vg9Vd2 T cells were defined recently (46).…”

“…The requirements for the differentiation of IL-17-producing human Vg9Vd2 T cells were defined recently (46). In addition to IL-1b, IL-6, TGF-b, and IL-23 must be present to enable the efficient differentiation of gd T cells that exclusively produce IL-17.…”

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

“…Therefore, we next investigated whether cytokines known to induce IL-17 production in mature γδ T-cells also participate in the programming of the γδ17 effector fate. Previous work suggested that γδ17 cells differ from their Th17 counterparts in terms of cytokine requirements, with IL-1β, IL-21, and IL-23 implicated as drivers of IL-17 production by γδ17 cells, whereas IL-6 is a key cytokine for Th17 cells 17–19, 32–35 . Therefore, we assessed whether adding combinations of IL-1β, IL-21, and IL-23 to the KN6/MEF co-cultures could result in the functional programming of the γδ17-effector subtype.…”

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…Activated Vc9/Vd2 T cells in fact induce chemotaxis and phagocytosis of neutrophils [85,86], and in return microbial compounds released by neutrophils upon phagocytosis of different pathogens are sensed by Vc9/Vd2 T cells [9,10], suggesting an intimate crosstalk of the two cell types, typically leading to their mutual activation. However, recent supports also suggest that under certain conditions neutrophils may actually suppress Vc9/Vd2 T cell responses [87,88], indicative of a fine-tuned regulatory interplay between the two cell types depending on the microenvironment [89].…”