NDLI: IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Völkl, Simon Ekici, Arif B. Gerbitz, Armin Mackensen, Andreas Allgäuer, Andrea Ferrazzi, Fulvia Schreiner, Elisabeth
Description	Author Affiliation: Allgäuer A ( Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany); Schreiner E ( Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany); Ferrazzi F ( Institute of Human Genetics, University Hospital Erlangen, 91054 Erlangen, Germany.); Ekici AB ( Institute of Human Genetics, University Hospital Erlangen, 91054 Erlangen, Germany.); Gerbitz A ( Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany); Mackensen A ( Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany); Völkl S ( Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany)
Abstract	Recently, a novel subset of TCR ß(+) CD4(-) CD8(-) double-negative (DN) T cells was described to suppress immune responses in both mice and humans. Moreover, in murine models, infusion and/or activation of DN T cells specifically suppressed alloreactive T cells and prevented the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. We demonstrated that human DN T cells, like their murine counterparts, are highly potent suppressor cells of both CD4(+) and CD8(+) T cell responses. After hematopoietic stem cell transplantation and other lymphopenic conditions, IL-7 plays an important role in the reconstitution, survival, and homeostasis of the T cell compartment. Because IL-7 was shown to interfere with T cell functionality, we asked whether IL-7 affects the functionality of human DN T cells. Intriguingly, IL-7 diminished the suppressive activity of DN T cells toward allogeneic CD4(+) effector T cells. Of interest, our studies revealed that IL-7 activates the Akt/mechanistic target of rapamycin (mTOR) pathway in human DN T cells. Importantly, selective inhibition of the protein kinases Akt or mTOR reversed the IL-7 effect, thereby restoring the functionality of DN T cells, whereas inhibition of other central T cell signaling pathways did not. Further analyses suggest that the IL-7/Akt/mTOR signaling cascade downregulates anergy-associated genes and upregulates activation- and proliferation-associated factors that may be crucial for DN T cell functionality. These findings indicate that IL-7 and Akt/mTOR signaling are critical factors for the suppressive capacity of DN T cells. Targeting of these pathways by pharmacological agents may restore and/or enhance DN T cell functionality in graft-versus-host disease.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	7
Volume Number	195
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2015-10-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Immune Tolerance Immunology Interleukin-7 Proto-oncogene Proteins C-akt Receptors, Antigen, T-cell, Alpha-beta Tor Serine-threonine Kinases Antigens, Cd4 Genetics Antigens, Cd8 Cd4-positive T-lymphocytes Cd8-positive T-lymphocytes Cell Proliferation Cells, Cultured Graft Vs Host Disease Hematopoietic Stem Cell Transplantation Lymphocyte Activation Antagonists & Inhibitors Signal Transduction Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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