Rapamycin increases the yield and effector function of human γδ T cells stimulated in vitro
- 25 November 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 60 (3), 361-370
- https://doi.org/10.1007/s00262-010-0945-7
Abstract
Clinical strategies to exploit Vγ2Vδ2 T cell responses for immunotherapy are confronted with short-term increases in cell levels or activity and the development of anergy that reduces the response to therapy with succeeding treatments. We are exploring strategies to increase the yield and durability of elicited Vγ2Vδ2 T cell responses. One approach focuses on the mammalian target of rapamycin (mTOR), which is important for regulating T cell metabolism and function. In Vγ2Vδ2 T cells, mTOR phosphorylates the S6K1 and eIF4EBP1 signaling intermediates after antigen stimulation. Rapamycin inhibited these phosphorylation events without impacting Akt or Erk activation, even though specific inhibition of Akt or Erk in turn reduced the activation of mTOR. The effects of rapamycin on the T cell receptor signaling pathway lead to increased proliferation of treated and antigen-exposed Vγ2Vδ2 cells. Rapamycin altered the phenotype of antigen-specific Vγ2Vδ2 cells by inducing a population shift from CD62L + CD69− to CD62L-CD69+, higher expression of CD25 or Bcl-2, lower levels of CCR5 and increased resistance to Fas-mediated cellular apoptosis. These changes were consistent with rapamycin promoting cell activation while decreasing the susceptibility to cell death that might occur by CCR5 or Fas signaling. Rapamycin treatment during antigen-stimulation of Vγ2Vδ2 T cells may be a strategy for overcoming current obstacles in tumor immunotherapy.Keywords
This publication has 48 references indexed in Scilit:
- mTOR and GSK-3 shape the CD4+ T-cell stimulatory and differentiation capacity of myeloid DCs after exposure to LPSBlood, 2010
- Effects of 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) and Rosiglitazone on Human Vδ2+ T CellsPLOS ONE, 2009
- Differential Responses of Human Regulatory T Cells (Treg) and Effector T Cells to RapamycinPLOS ONE, 2009
- mTOR regulates memory CD8 T-cell differentiationNature, 2009
- Immunoregulatory functions of mTOR inhibitionNature Reviews Immunology, 2009
- Isopentenyl Pyrophosphate–Activated CD56+ γδ T Lymphocytes Display Potent Antitumor Activity toward Human Squamous Cell CarcinomaClinical Cancer Research, 2008
- Impacts of HIV infection on Vγ2Vδ2 T cell phenotype and function: a mechanism for reduced tumor immunity in AIDSJournal of Leukocyte Biology, 2008
- Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte traffickingNature Immunology, 2008
- The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cellsThe Journal of Experimental Medicine, 2008
- Human V 2V 2 T cells contain cytoplasmic RANTESInternational Immunology, 2006