The gene expression profile of phosphoantigen‐specific human <b>γδ</b> T lymphocytes is a blend of αβ T‐cell and NK‐cell signatures

Pont, Frédéric; Familiadès, J; Déjean, Sébastien; Fruchon, Séverine; Cendron, Delphine; Poupot, Mary; Poupot, Rémy; L’Faqihi-Olive, Fatima; Prade, Naïs; Ycart, Bernard; Fournié, Jean‐Jacques

doi:10.1002/eji.201141870

Cited by 48 publications

(52 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This study adds a further facet to the pattern of Vδ2 T-cell gene expression, which has been described as being intermediate between αβ T cells and natural killer cells (26). The results of our present investigation extend these previous studies by demonstrating that gene expression is differentially regulated in human Vδ2 T cells by cognate TCR antigen BrHPP and A/E beads, and TGF-β/IL-15 cytokines provide an additional layer of regulation.…”

Section: Discussionsupporting

confidence: 81%

Human Vδ2 T cells are a major source of interleukin-9

Peters

Häsler

Wesch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Vδ2Vγ9 T cells are the dominant γδ T-cell subset in human peripheral blood. Vδ2 T cells recognize pyrophosphate molecules derived from microbes or tumor cells; hence, they play a role in antimicrobial and antitumor immunity. TGF-β, together with IL-15, induces a regulatory phenotype in Vδ2 T cells, characterized by forkhead box protein P3 (FoxP3) expression and suppressive activity on CD4 T-cell activation. We performed a genome-wide transcriptome analysis and found that the same conditions (TGF-β plus IL-15) strongly enhanced the expression of additional genes in Vδ2 T cells, including IKAROS family zinc finger 4 (IKZF4; Eos), integrin subunit alpha E (ITGAE; CD103/αEβ7), and IL9. This up-regulation was associated with potent IL-9 production as revealed by flow cytometry and multiplex analysis of cell culture supernatants. In contrast to CD4 and CD8 αβ T cells, γδ T cells did not require IL-4 for induction of intracellular IL-9 expression. Upon antigen restimulation of Vδ2 T cells expanded in vitro in the presence of TGF-β and IL-15, IL-9 was the most abundant among 16 analyzed cytokines and chemokines. IL-9 is a pleiotropic cytokine involved in various (patho)physiological conditions, including allergy and tumor defense, where it can promote antitumor immunity. Given the conspicuous sensitivity of many different tumors to Vδ2 T-cell–mediated killing, the conditions defined here for strong induction of IL-9 might be relevant for the development of Vδ2 T-cell–based immunotherapy.

show abstract

Section: Discussionsupporting

confidence: 81%

Human Vδ2 T cells are a major source of interleukin-9

Peters

Häsler

Wesch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…GSE27291) and six adult blood αβ T-cell samples (accession nos. GSE15659 and GSE8059) were obtained from the National Center for Biotechnology Information Gene Expression Omnibus (55). Primers to quantify gene expression within sorted Vγ9Vδ2 γδ T cells, non-Vγ9Vδ2 γδ T cells, and αβ T cells were selected from PrimerBank (91) or were designed using Primer Express 2.0 (Applied Biosystems) (SI Appendix.…”

Section: Methodsmentioning

confidence: 99%

“…Several adapter proteins [DNAX-activation protein 10 (DAP10), DAP12] and signaling molecules, such as phospholipase C, gamma 2 (PLCG2), PI3K, and CD3zeta, described as being associated with NKR signaling, were enriched as well (SI Appendix, Table S6) (54). Th1 bias, proinflammatory nature, and enrichment in NK genes also have been described as selective features of adult Vγ9Vδ2 T cells as compared with adult αβ T cells (55); comparison with adult Vγ9Vδ2 T-cellenriched genes showed that indeed several also were enriched in fetal Vγ9Vδ2 T cells (SI Appendix, Table S9). Vice versa, various fetal Vγ9Vδ2 T-cell-enriched genes (such as a series of transcription factors including PLZF) but not all (e.g., DAP10 and granzyme A) also were enriched in adult Vγ9Vδ2 T cells (SI Appendix, Table S6).…”

Section: Fetal Blood Cdr3γ9 Is Highly Restricted and Enriched For Thementioning

confidence: 99%

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

Dimova

Brouwer

Gosselin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

187

215

View full text Add to dashboard Cite

γδ T cells are unconventional T cells recognizing antigens via their γδ T-cell receptor (TCR) in a way that is fundamentally different from conventional αβ T cells. γδ T cells usually are divided into subsets according the type of Vγ and/or Vδ chain they express in their TCR. T cells expressing the TCR containing the γ-chain variable region 9 and the δ-chain variable region 2 (Vγ9Vδ2 T cells) are the predominant γδ T-cell subset in human adult peripheral blood. The current thought is that this predominance is the result of the postnatal expansion of cells expressing particular complementary-determining region 3 (CDR3) in response to encounters with microbes, especially those generating phosphoantigens derived from the 2-C-methyl-d-erythritol 4-phosphate pathway of isoprenoid synthesis. However, here we show that, rather than requiring postnatal microbial exposure, Vγ9Vδ2 T cells are the predominant blood subset in the second-trimester fetus, whereas Vδ1+ and Vδ3+ γδ T cells are present only at low frequencies at this gestational time. Fetal blood Vγ9Vδ2 T cells are phosphoantigen responsive and display very limited diversity in the CDR3 of the Vγ9 chain gene, where a germline-encoded sequence accounts for >50% of all sequences, in association with a prototypic CDR3δ2. Furthermore, these fetal blood Vγ9Vδ2 T cells are functionally preprogrammed (e.g., IFN-γ and granzymes-A/K), with properties of rapidly activatable innatelike T cells. Thus, enrichment for phosphoantigen-responsive effector T cells has occurred within the fetus before postnatal microbial exposure. These various characteristics have been linked in the mouse to the action of selecting elements and would establish a much stronger parallel between human and murine γδ T cells than is usually articulated.

show abstract

“…Transcriptome raw data files were downloaded from the GSE27291 dataset available at the National Center for Biotechnology Information repository Gene Expression Omnibus database (39). These comprised 12 samples of TCRVg9 + gd cells highly purified (.98% purity) from PBMC: four "resting control" samples, four "6 h after BrHPP activation" samples, and four "7 d after BrHPP activation" samples.…”

Section: Il1rl1 Gene Expression Analysismentioning

confidence: 99%

TCRVγ9 γδ T Cell Response to IL-33: A CD4 T Cell–Dependent Mechanism

Duault

Franchini

Familliades

et al. 2016

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The availability of specific stimuli to induce the anticancer cytotoxicity of human TCRVγ9-expressing T lymphocytes has allowed the development of γδ T cell–based cancer immunotherapies. However, the stringent dependence of such strategies on the inherently toxic IL-2 has raised safety concerns for patients, justifying a search for alternative methods for inducing γδ T cell stimulation. IL-33 is a γ-chain receptor-independent cytokine of the IL-1 superfamily that is expressed by endothelial cells from a tumor microenvironment and can sustain Th1 and Th2 immune responses. Therefore, we investigated its ability to support the stimulation of human TCRVγ9+ γδ T cells. In this study, we report that IL-33 efficiently sustained the in vitro activation of Vγ9 T lymphocytes by synthetic phosphoantigens, zoledronate, and a BTN3A1 Ab in the absence of an exogenous supply of IL-2. IL-33 was as potent as IL-2 in allowing the proliferative amplification of Vγ9 T cells isolated from PBMC following activation by the synthetic phosphoantigen bromohydrin pyrophosphate. IL-33 also induced an identical maturation into TNF-α– and IFN-γ–producing Th1 effector memory cells, and IL-33–stimulated cells showed an equivalent cytotoxicity for various tumor cells in vitro. Finally, we found that the bioactivity of IL-33 on the Vγ9 T cell was indirectly mediated through contact with CD4 T cells and IL-2 production by CD4 T cells and Vγ9 T cells themselves. These data posit IL-33 as an alternative to IL-2 for Vγ9 T cell–based cancer immunotherapies.

show abstract

The gene expression profile of phosphoantigen‐specific human γδ T lymphocytes is a blend of αβ T‐cell and NK‐cell signatures

Cited by 48 publications

References 57 publications

Human Vδ2 T cells are a major source of interleukin-9

Human Vδ2 T cells are a major source of interleukin-9

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

TCRVγ9 γδ T Cell Response to IL-33: A CD4 T Cell–Dependent Mechanism

Contact Info

Product

Resources

About