1. TGF-beta in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus.
- Author
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Cumont MC, Monceaux V, Viollet L, Lay S, Parker R, Hurtrel B, and Estaquier J
- Subjects
- Animals, Apoptosis Regulatory Proteins pharmacology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes metabolism, Cell Proliferation, Disease Progression, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Intestines virology, Lymph Nodes virology, Macaca mulatta, Simian Acquired Immunodeficiency Syndrome etiology, Simian Acquired Immunodeficiency Syndrome metabolism, Tumor Suppressor Protein p53 metabolism, Apoptosis physiology, CD8-Positive T-Lymphocytes pathology, Intestinal Mucosa metabolism, Lymph Nodes metabolism, Simian Acquired Immunodeficiency Syndrome pathology, Simian Immunodeficiency Virus pathogenicity, Transforming Growth Factor beta metabolism
- Abstract
SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8+ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8+ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-beta and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8+ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8+ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/memory CD8+ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1+ expressing cells. Finally, we provide evidence that abrogation of TGF-beta in vitro enhances T-cell proliferation and reduces CD8+ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS.
- Published
- 2007
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