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-β 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-β 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.
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Abbreviations
- AIDS:
-
Acquired Immunodeficiency Syndrome
- SIV:
-
Simian Immunodeficiency Virus
- HIV:
-
Human Immunodeficiency Virus
- LN:
-
lymph node
- IDO:
-
indoleamine 2,3 dioxygenase
- GALT:
-
gut-associated lymphoid tissue
- PD-1:
-
programmed death 1
- AICD:
-
activation-induced cell death
- CTL:
-
cytotoxic T lymphocyte
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Acknowledgements
The authors are grateful to Dr. J Berzofsky (National Cancer Institute, Bethesda, USA) and Dr. Y Lévy (Hôpital Henri-Mondor, Créteil, France) for critically reading the manuscript and for helpful comments. We also acknowledge JM Panaud (Institut Pasteur) for pictures and AM Aubertin (INSERM U-74, Strasbourg) for kindly providing virus. We apologize to the authors of relevant articles that are not cited because of space limitations. This work was funded by grants from the Agence Nationale de la Recherche sur le Sida (ANRS) and Fondation de la Recherche Médicale (FRM) to JE. VL was supported by a fellowship from ANRS and LS by a postdoctoral fellowship from SIDACTION.
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Cumont, M., Monceaux, V., Viollet, L. et al. TGF-β 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. Cell Death Differ 14, 1747–1758 (2007). https://doi.org/10.1038/sj.cdd.4402192
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DOI: https://doi.org/10.1038/sj.cdd.4402192
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