Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway.

BMC Immunology
Olga V Efimova, Todd W Kelley

Abstract

Regulatory T cells (Tregs) can employ a cell contact- and granzyme B-dependent mechanism to mediate suppression of bystander T and B cells. Murine studies indicate that granzyme B is involved in the Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment and in the Treg-mediated maintenance of allograft survival. In spite of its central importance, a detailed study of granzyme B expression patterns in human Tregs has not been performed. Our data demonstrated that natural Tregs freshly isolated from the peripheral blood of normal adults lacked granzyme B expression. Tregs subjected to prolonged TCR and CD28 triggering, in the presence of IL-2, expressed high levels of granzyme B but CD3 stimulation alone or IL-2 treatment alone failed to induce granzyme B. Treatment of Tregs with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin or the PI3 kinase (PI3K) inhibitor LY294002 markedly suppressed granzyme B expression. However, neither rapamycin, as previously reported by others, nor LY294002 inhibited Treg proliferation or induced significant cell death in TCR/CD28/IL-2 stimulated cells. The proliferation rate of Tregs was markedly higher than that of CD4+ conventional T cells in the setting of rap...Continue Reading

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Citations

Nov 3, 2011·Clinical & Developmental Immunology·Francesco DituriSalvatore Antonaci
Nov 2, 2014·Cancer Metastasis Reviews·Elizabeth C HalvorsenKevin L Bennewith
May 8, 2015·Oncoimmunology·Stefanie KoristkaMichael P Bachmann
Jun 14, 2015·Journal of the National Cancer Institute·Gongda XueBrian A Hemmings
Dec 1, 2017·Frontiers in Immunology·Wei-Cheng YangChia-Rui Shen
Feb 9, 2017·Frontiers in Immunology·Jennifer A JunoC Mee Ling Munier
Apr 6, 2019·Current Medicinal Chemistry·Shahram GolbabapourBita Geramizadeh

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Methods Mentioned

BETA
blood collection
density gradient centrifugation
flow cytometry
flow
transfection

Software Mentioned

FloJo
FACSDiva

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