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J Immunol. 2016 Jan 1;196(1):493-502. doi: 10.4049/jimmunol.1500260. Epub 2015 Nov 25.

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

Author information

1
INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse, 31037 Toulouse, France; Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; CNRS ERL 5294, 31024 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and.
2
Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and CNRS UMR 5089, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
3
INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse, 31037 Toulouse, France; Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; CNRS ERL 5294, 31024 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and mary.poupot@inserm.fr.

Abstract

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.

PMID:
26608919
DOI:
10.4049/jimmunol.1500260
[Indexed for MEDLINE]
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