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

Cell Death Differ. 2007 Oct;14(10):1747-58. doi: 10.1038/sj.cdd.4402192. Epub 2007 Jul 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / pharmacology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology*
  • Cell Proliferation
  • Disease Progression
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Intestinal Mucosa / metabolism*
  • Intestines / virology
  • Lymph Nodes / metabolism*
  • Lymph Nodes / virology
  • Macaca mulatta
  • Simian Acquired Immunodeficiency Syndrome / etiology
  • Simian Acquired Immunodeficiency Syndrome / metabolism
  • Simian Acquired Immunodeficiency Syndrome / pathology*
  • Simian Immunodeficiency Virus / pathogenicity*
  • Transforming Growth Factor beta / metabolism*
  • Tumor Suppressor Protein p53 / metabolism


  • Apoptosis Regulatory Proteins
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53