Cytomegalovirus-Infected Human Endothelial Cells Can Stimulate Allogeneic CD4+Memory T Cells by Releasing Antigenic Exosomes

ABSTRACT Human endothelial cells (ECs) enhance human immunodeficiency virus (HIV) replication within CD4+ memory T cells by 50,000-fold in a Nef-dependent manner. Here, we report that EC-mediated HIV type 1 replication is also dependent on an intact vpr gene. Moreover, we demonstrate that despite a requirement for engaging major histocompatibility complex (MHC) class II molecules and costimulators, EC-stimulated virus-producing cells (p24high T cells) do not proliferate, nor are they arrested in the cell cycle. Rather, they are minimally activated, sometimes expressing CD69 but not CD25, HLA-DR, VLA-1, or effector cytokines. Blocking antibodies to interleukin 2 (IL-2), IL-6, IL-7, or tumor necrosis factor do not inhibit viral replication. Cyclosporine effectively inhibits viral replication, as does disruption of the NFAT binding site in the viral long terminal repeat. Furthermore, in the presence of ECs, suboptimal T-cell receptor (TCR) stimulation with phytohemagglutinin L supports efficient viral replication, and suboptimal stimulation with toxic shock syndrome toxin 1 leads to viral replication selectively in the TCR-stimulated, Vβ2-expressing T cells. Collectively, these data indicate that ECs provide signals that promote Nef- and Vpr-dependent HIV replication in memory T cells that have been minimally activated through their TCRs. Our studies suggest a mechanism for HIV replication in vivo within the reservoir of circulating memory CD4+ T cells that persist despite antiretroviral therapy and further suggest that maintenance of immunological memory by MHC class II-expressing ECs via TCR signaling may contribute to HIV rebound following cessation of antiretroviral therapy.

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Single-Cell Analysis of Costimulation by B Cells, Endothelial Cells, and Fibroblasts Demonstrates Heterogeneity in Responses of CD4+ Memory T Cells

Cellular Immunology ◽

10.1006/cimm.1999.1504 ◽

1999 ◽

Vol 194 (2) ◽

pp. 150-161 ◽

Cited By ~ 16

Author(s):

Lisa L. Salazar Murphy ◽

Melissa M. Mazanet ◽

Angela C. Taylor ◽

Javier Mestas ◽

Christopher C.W. Hughes

Keyword(s):

T Cells ◽

Endothelial Cells ◽

B Cells ◽

Single Cell ◽

Single Cell Analysis ◽

Memory T Cells ◽

Cell Analysis

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Abstract 561: GITR Activation Promotes Regulatory CD4+ T-cell Responses and Stimulates Leukocyte Recruitment in Atherosclerotic Plaques

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.561 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Annelie Shami ◽

Svenja Meiler ◽

Holger Winkels ◽

Norbert Gerdes ◽

Esther Lutgens

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Regulatory T Cells ◽

B Cell ◽

Memory T Cells ◽

Effector Memory ◽

Wild Type ◽

Atherosclerotic Lesions ◽

Effector Memory T Cells ◽

Antigen Presenting

Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) - a costimulatory molecule - is expressed on CD4(+) effector memory T cells and regulatory T cells as well as antigen-presenting cells and mast cells; while its ligand (GITRL) is mainly found on antigen-presenting cells and endothelial cells. However, the definitive role of GITR in atherosclerosis is not fully understood. Our hypothesis is that signaling through GITR plays a vital role in atherosclerosis progression. Low-density lipoprotein receptor-deficient mice (Ldlr -/- ) with B-cell-restricted overexpression of GITRL ( Gitrl tg ) fed a high-cholesterol diet showed a profound increase in both CD4(+) effector memory T cells and regulatory T cells in secondary lymphoid organs in comparison to wild-type controls. Additionally, the number of regulatory T cells was significantly enhanced in the thymus and aorta of these mice along with increased GITRL and interleukin-2 transcript levels. Atherosclerotic lesions of Ldlr -/- Gitrl tg mice contained more total CD3 + T cells as well as Foxp3 + regulatory T cells overall, leading to significantly less severe atherosclerosis. Conversely, atherosclerosis was found to be less severe in mice deficient in apolipoprotein E and GITR (ApoE -/- GITR -/- ). Atherosclerotic lesions in these mice were found to contain less macrophages and CD3-positive T-cells. Perfusion assays using two-photon excitation microscopy revealed less wild type leukocyte adhesion on GITR-deficient endothelium, with a further reduction in adhesion by GITR-deficient leukocytes to both wild type and GITR-deficient endothelia. Finally, expression of GITR expression in human plaque tissue was significantly increased in ruptured plaques. In conclusion, these data indicate that continuous GITR stimulation through B cell GITRL acts protective in a mouse model of atherosclerosis by regulating the balance between regulatory and effector memory CD4(+) T cells, while GITR activation on endothelial cells promotes atherogenesis by stimulating leukocyte recruitment into the plaque.

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