Potentiation of Antigen-Stimulated Vγ9Vδ2 T Cell Cytokine Production by Immature Dendritic Cells (DC) and Reciprocal Effect on DC Maturation

Abstract

Vγ9Vδ2 T cells, a major γδ PBL subset in human adults, have been previously implicated in dendritic cell (DC) licensing, owing to their high frequency in peripheral tissues and their ability to produce inflammatory cytokines upon recognition of a broad array of conserved Ags. Although these observations implied efficient recognition of Ag-expressing immature DC (iDC) by Vγ9Vδ2 T cells, the role played by DC subsets in activation of these lymphocytes has not been carefully studied so far. We show that iDC, and to a lesser extent mature DC, potentiated Th1 and Th2 cytokine, but not cytolytic or proliferative responses, of established Vγ9Vδ2 T cell clones and ex vivo memory Vγ9Vδ2 PBL stimulated by synthetic agonists. The ability of iDC to potentiate Vγ9Vδ2 production of inflammatory cytokines required for their own maturation suggested that Vγ9Vδ2 T cells, despite their strong lytic activity, could promote efficient iDC licensing without killing at suboptimal Ag doses. Accordingly Vγ9Vδ2 cells induced accelerated maturation of Ag-expressing iDC but not “bystander” DC, even within mixed cell populations comprising both Ag-expressing and nonexpressing iDC. Furthermore Vγ9Vδ2 cells induced full differentiation into IL-12-producing cells of iDC infected by Vγ9Vδ2-stimulating mycobacteria that were otherwise unable to induce complete DC maturation. In conclusion the ability of iDC to selectively potentiate cytokine response of memory Vγ9Vδ2 T cells could underlie the adjuvant effect of these lymphocytes, and possibly other natural memory T cells, on conventional T cell responses.

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

“…Not only are phosphoantigen-activated Vg9Vd2 cells high producers of Th1 cytokines and very cytotoxic against a variety of tumors [54], but they can also induce DC maturation [55], and even perform as CD80/86-expressing APC [56]. While the recent characterization of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a very potent agonist of Vg9Vd2 responses [57,58] strengthens the principle of gd-cellbased immunotherapy, the data we report here, by clarifying how gd-cell activities can be negatively modulated, stress the importance of combining Treg inhibition with gd-cell activation for future immunotherapeutic strategies.…”

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

“…In return, DCs have been shown to activate Vc9/Vd2 T cells via TCR-independent mechanisms, predominantly by the release of type I IFNs [33][34][35]. Effects on Vc9/Vd2 T cells include the induction and enhancement of proliferation [36] and the expression of cytotoxic and pro-inflammatory mediators such as perforin, IFN-c and TNF-a [34,37,38], thereby forming a positive feedback loop for mutual stimulation of both cell types.…”

“…Ismaili and colleagues [39] were the first to report that activated Vc9/Vd2 T cells stimulate the upregulation of HLA-DR, CD86 and CD83 on immature DCs, in the absence of other stimuli. Further Vc9/Vd2 T cell-induced APC markers on DCs may include MHC class I, CD25, CD40, CD80 and others, depending on the culture conditions [37,[40][41][42], suggesting a certain degree of plasticity under the influence of the microenvironment, albeit with unclear physiological implications. Besides inducing DC maturation on their own, Vc9/Vd2 T cell-derived factors also synergize with other signals and as such enhance DC maturation triggered by TLR ligands [40,41,43].…”

“…In this context, DCs infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) undergo maturation by Vc9/Vd2 T cells, activated either with zoledronate/ phosphoantigens or by the BCG infected DCs themselves [37,46]. Meraviglia et al [47] reported that DCs, partially matured upon infection with Mycobacterium tuberculosis, were able to activate Vc9/Vd2 T cells and become fully matured in return.…”

“…In return, DCs have been shown to activate Vc9/Vd2 T cells via TCR-independent mechanisms, predominantly by the release of type I IFNs [33][34][35]. Effects on Vc9/Vd2 T cells include the induction and enhancement of proliferation [36] and the expression of cytotoxic and pro-inflammatory mediators such as perforin, 37,38], thereby forming a positive feedback loop for mutual stimulation of both cell types.Upregulation of APC markers and co-stimulatory molecules is an important step in the DC maturation process, due to their vital role in triggering appropriate adaptive responses to any given challenge. Ismaili and colleagues [39] were the first to report that activated Vc9/Vd2 T cells stimulate the upregulation of HLA-DR, CD86 and CD83 on immature DCs, in the absence of other stimuli.…”