In vivo analysis of Fas/FasL interactions in HIV-infected patients.

Badley, Andrew D.; Dockrell, David H.; Algeciras, Alicia; Ziesmer, Steve; Landay, Alan; Lederman, Michael M.; Connick, Elizabeth; Kessler, Harold A.; Kuritzkes, Daniel R.; Lynch, David H.; Roche, Patrick C.; Yagita, Hideo; Payá, Carlos V.

doi:10.1172/jci2691

Cited by 148 publications

(101 citation statements)

References 42 publications

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“…CD95L expression has been reported to increase during HIV [32][33][34] and SIV infections. 35 CD95L mRNA levels were significantly higher in PBMC from macaques infected with SIVmac251 or Dnef than in uninfected animals ( Figure 5a).…”

Section: Spontaneous Death Of T Cells From Sivmac251-infected Macaquementioning

confidence: 99%

Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression

et al. 2003

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Studies of human immunodeficiency virus (HIV) and nonhuman primate models of pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections have suggested that enhanced ex vivo CD4 T-cell death is a feature of pathogenic infection in vivo. However, the relative contributions of the extrinsic and intrinsic pathways to programmed T-cell death in SIV infection have not been studied. We report here that the spontaneous death rate of CD4 þ T cells from pathogenic SIVmac251-infected rhesus macaques ex vivo is correlated with CD4 T-cell depletion and plasma viral load in vivo. CD4 þ T cells from SIVmac251-infected macaques showed upregulation of the death ligand (CD95L) and of the proapoptotic proteins Bim and Bak, but not of Bax. Both CD4 þ and CD8 þ T cells from SIVmac251-infected macaques underwent caspase-dependent death following CD95 ligation. The spontaneous death of CD4 þ and CD8 þ T cells was not prevented by a decoy CD95 receptor or by a broad-spectrum caspase inhibitor (zVADfmk), suggesting that this form of cell death is independent of CD95/CD95L interaction and caspase activation. IL-2 and IL-15 prevented the spontaneous death of CD4 þ and CD8 þ T cells, whereas IL-10 prevented only CD8 T-cell death and IL-7 had no effect on T-cell death. Our results indicate that caspasedependent and caspase-independent pathways are involved in the death of T cells in pathogenic SIVmac251-infected primates.

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Section: Spontaneous Death Of T Cells From Sivmac251-infected Macaquementioning

confidence: 99%

Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression

et al. 2003

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“…The sensitivity of these cells to apoptosis may be influenced by many factors, including the functional state of CD95 (Peter et al, 1997) as well as the presence of FasL necessary for crosslinking of the receptor (Ju et al, 1995). While the Fas/FasL pathway appears to participate in inducing apoptosis of CD4+ T cells in HIV (Badley et al, 1998) and of CD8+ T cells in cancer (Saito et al, 2000;Dworacki et al, 2001;Hoffmann et al, 2002), it is clearly not the only mechanism responsible for elimination of activated T cells. Among other factors that have been suggested are TNF/TNF-R, TRAIL/TRAIL-R (Srivastava, 2001), tumour-derived soluble factors (Taylor et al, 2001), and reactive oxygen metabolites (Hansson et al, 1999;Schmielau and Finn, 2001).…”

Section: Discussionmentioning

confidence: 99%

Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer

et al. 2003

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Prolactin (PRL) has been reported to inhibit apoptosis in various cell types and to serve as a cofactor in the upregulation of CD25 on T cells during activation. We investigated a possible relation between prolactin receptor (PRL-R) or IL-2 receptor alpha (IL-2Ra, CD25) expression on circulating T lymphocytes and their apoptosis in patients with breast cancer. Peripheral blood mononuclear cells obtained from 25 patients, 25 normal controls (NC) and three cord blood samples were evaluated for Annexin V binding and expression of CD95, CD25, and PRL-R on CD3 + T cells by multicolour flow cytometry. Plasma levels of PRL, sCD95L, and sIL-2R were determined in patients and controls and related to T-cell apoptosis. The ability of PRL to protect T cells from apoptosis induced by various agents was also studied. Expression of PRL-R on the surface of T cells was comparable in patients with breast cancer and NC, but PRL plasma levels in patients were significantly lower (Po0.05). In patients, 18711% (mean7s.d.) of CD3 + cells bound Annexin V, compared to 976% in NC (Po0.0004). Percentages of CD3 + Fas + and CD3 + CD25 + cells were higher in the peripheral circulation of patients than NC (Po0.0001 and o0.04, respectively). Levels of sFasL were lowest in plasma of the patients with the highest proportions of CD3 + Fas + T cells. Most T cells undergoing apoptosis were CD3 + CD25 À in patients, and the proportion of CD3 + CD25 À Annexin V + cells was significantly increased in patients compared to NC (Po0.006). Ex vivo PRL protected T cells from starvation-induced or anti-CD3Ab-induced but not from Fas/FasL-dependent apoptosis. These results indicate that expression of CD25 but not of PRL-R on the surface of activated T lymphocytes appears to be involved in modulating Fas/Fas -ligand interactions, which are, in part, responsible for apoptosis of T lymphocytes and excessive turnover of immune cells in the circulation of patients with breast cancer.

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“…55 Importantly, the magnitude of CD4 þ T-cell apoptosis observed in HIV-infected individuals correlates well with the stage of HIV disease. [56][57][58][59][60][61] In addition, changes in the levels of T-cell apoptosis after highly active antiretroviral therapy (HAART) predict the immunological response (i.e., increase in CD4 T-cell count), thus confirming the link between disease progression and apoptosis. [62][63][64] Taken together, these observations indicate that the increased susceptibility to apoptosis of T lymphocytes from HIV-infected individuals is a marker of HIV disease progression and support the hypothesis that the chronic immune system activation that Figure 2 Overview of apoptosis pathway.…”

Section: T-cell Apoptosis and Aidsmentioning

confidence: 91%

“…T-cell activation occurring in the course of immune responses has been shown to increase sensitivity to CD95-induced apoptosis. Antiretroviral therapy is followed by a significant decrease in CD95-induced, activation-induced, and spontaneous apoptosis in ex vivo cultured peripheral blood lymphocytes 60,96 which correlates with decreased immune activation. 105 Thus, effective viral suppression decreases immune activation and apoptosis, thereby contributing to immune reconstitution.…”

Section: Activation-induced Cell Deathmentioning

confidence: 99%