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2410 Human Double-Negative Regulatory T Cells Modulate Effector Functions of Conventional T Cells By Selectively Blocking mTOR Signaling

Program: Oral and Poster Abstracts
Session: 203. Lymphocytes, Lymphocyte Activation, and Immunodeficiency, including HIV and Other Infections: Poster II
Hematology Disease Topics & Pathways:
Diseases, Biological, Therapies, GVHD, Biological Processes, Immune Disorders, immunotherapy, immune mechanism, signal transduction
Sunday, December 2, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Tabea Haug1*, Michael Aigner, PhD1*, Heiko Bruns, PhD1*, Moritz Peuser1*, Dorothea Gebhardt1*, Jana Berger1*, Florentine Koppitz1*, Andreas Mackensen, MD2* and Simon Voelkl1*

1University of Erlangen-Nuernberg - Hematology/Oncology, Erlangen, Germany
2Department of Internal Medicine 5 - Hematology/Oncology, University Hospital of Erlangen, Erlangen, Germany

Regulatory T cells play an important role in the maintenance of immune tolerance to self-antigens and are involved in modulating immune responses to promote resolution of inflammation. The population of TCRαβ+ CD4-/CD8- (double-negative, DN) T cells has attracted growing attention as a result of their potent immune regulatory function. In murine models, DN T cells were able to prevent rejection of allogeneic and xenogeneic organ grafts by effectively suppressing reactive T cells. In addition, DN T cells possess the capacity to resolve various inflammatory conditions, including graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation. Notably, first clinical studies in patients after stem cell transplantation demonstrated an inverse correlation between the frequency of circulating DN T cells and the severity of acute GvHD, suggesting a therapeutic potential of human DN T cells. To gain a better understanding of the molecular mechanism of suppression, we investigated whether human DN T cells modulate distinct signaling processes in conventional T cells. We found that DN T cells selectively block mTOR signaling but not activation of mitogen-activated protein kinases. Enforced activation of the mTOR pathway by a chemical activator rendered conventional T cells unsusceptible to DN T cell-mediated suppression, confirming the critical function of mTOR signaling. Given that mTOR is a major regulator of cellular metabolism, we further determined the impact of DN T cells on the metabolic framework of conventional T cells. Of interest, DN T cells diminished upregulation of the glycolytic machinery and glucose uptake in conventional T cells, whereas fatty acid uptake was not modified. Next, we investigated the fate and function of effector cells after DN T cell co-culture. Of importance, DN T cells suppressed proliferation but also altered expression of differentiation markers, transcription factors and homing receptors. Further analyses demonstrated that CD4+ T cells failed to produce effector cytokines IL-17 and IFN-γ after coculture with DN T cells, whereas IL-2 secretion was amplified. The selective modification was induced by a direct cell-cell contact dependent mechanism between CD4 and DN T cells and not as a consequence of competition for nutrients or growth factors. Together, our findings expand the understanding of DN T cell functionality and support that human DN T cells represent an interesting opportunity to limit and modulate T-cell reactivity.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH