Y2K+1 state-of-the-art on non-peptide phosphoantigens, a novel category of immunostimulatory molecules

107

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.

Section: Ammalian Cd3mentioning

confidence: 99%

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

Devilder

Maillet

Bouyge-Moreau

et al. 2006

107

“…and hydrophilic structures. These comprise either natural or synthetic pyrophosphoesters referred to as phosphoantigens (33,34), therapeutic aminobisphosphonates (35), and natural or synthetic alkylamines (36). Natural phosphoantigens such as 3-formyl-1-butyl pyrophosphate (3fbPP) were isolated from various bacteria including Mycobacterium tuberculosis (37) and Escherichia coli (38).…”

Section: U Pon Ag Recognition B and T Cells Establish With Target Cementioning

confidence: 99%

Synaptic Transfer by Human γδ T Cells Stimulated with Soluble or Cellular Antigens

Espinosa

Tabiasco

Hudrisier

et al. 2002

B, αβ T, and NK lymphocytes establish immunological synapses (IS) with their targets to enable recognition. Transfer of target cell-derived Ags together with proximal molecules onto the effector cell appears also to occur through synapses. Little is known about the molecular basis of this transfer, but it is assumed to result from Ag receptor internalization. Because human γδ T cells recognize soluble nonpeptidic phosphoantigens as well as tumor cells such as Daudi, it is unknown whether they establish IS with, and extract molecules from, target cells. Using flow cytometry and confocal microscopy, we show in this work that Ag-stimulated human Vγ9/Vδ2 T cells conjugate to, and perform molecular transfer from, various tumor cell targets. The molecular transfer appears to be linked to IS establishment, evolves in a dose-dependent manner in the presence of either soluble or cellular Ag, and requires γδ TCR ligation, Src family kinase signaling, and participation of the actin cytoskeleton. Although CD45 exclusion characterized the IS performed by γδ T cells, no obvious capping of the γδ TCR was detected. The synaptic transfer mediated by γδ T cells involved target molecules unrelated to the cognate Ag and occurred independently of MHC class I expression by target cells. From these observations, we conclude thatm despite the particular features of γδ T cell activation, both synapse formation and molecular transfer of determinants belonging to target cell characterize γδ T cell recognition of Ags.

“…2). Recognition of these non-peptide Ags strictly depends on TCR interactions involving amino acid residues located on both the V␥9-and V␦2-CDR3 regions (3)(4)(5).…”

mentioning

confidence: 99%

Uncoupling between Immunological Synapse Formation and Functional Outcome in Human γδ T Lymphocytes

Favier¹,

Espinosa

Tabiasco

et al. 2003

Human T lymphocytes expressing the Vγ9Vδ2 TCR recognize non-peptidic Ags, referred to as phosphoantigens, produced by microbial pathogens and by human tumor cells. Here we show that γδ T cells establish a mature immunological synapse (IS) with the myelomonocytic THP-1 tumoral cell line. This synapse is characterized by an enrichment for phosphotyrosine, CD2, and γδ TCR together with the exclusion of CD45. The CD94 and NKG2D receptors are also recruited to the signaling area, while the C-lectin-like activation marker CD69 segregates out of the synapse. γδ T cell conjugation to THP-1 increases upon stimulation by soluble phosphoantigen, is paralleled by the metabolic activation of γδ T cells and leads to cytokine production. Molecular segregation of the above molecules also occurs at the γδ T cell/THP-1 interface in the absence of exogenously added phosphoantigen, although it does not result in intracellular signaling and cytokine production under these conditions. Hence the molecular interactions at the γδ T cell-THP-1 target cell interface are sufficient to induce the formation of an IS, but cytokine production requires the full engagement of γδ TCR by a strong agonist. Thus in γδ T cells, formation of the IS is uncoupled from its functional outcome.