PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors

Zhang, Jiyuan; Zhang, Zheng; Wang, Xicheng; Fu, Junliang; Yao, Jinxia; Jiao, Yanmei; Chen, Liangen; Zhang, Hui; Wei, Jianan; Jin, Lei; Shi, Ming; Gao, George F.; Wu, Hao; Wang, Fusheng

doi:10.1182/blood-2006-09-044826

Cited by 264 publications

(269 citation statements)

References 37 publications

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“…Consistent with recent studies in mice and humans, [5][6][7][8][9]27 our data confirm that blocking the PD-1/PD-L1 pathway has potential therapeutic value in tumor immunotherapy. At least in NSCLC conditions, blocking the PD-1/PD-L1 pathway was more effective than blocking the PD-1/PD-L2 pathway.…”

Section: Discussionsupporting

confidence: 91%

“…Increasing apoptosis of tumor-infiltrating CD8 1 T cells and blocking the PD-1/PD-L1 pathway cannot abrogate apoptosis Because PD-1 upregulation has been reported to be more sensitive to apoptosis, resulting in a deficiency of CD8 1 T cells in controlling virus replication, [6][7][8][9] we tested apoptosis of different CD8 1 T cells induced by anti-CD3. Tumor-infiltrating CD8 1 T cells exhibited much higher apoptosis rates than peripheral blood CD8 1 T cells from either healthy control or patients with NSCLC (all P,0.01; Figure 4a).…”

Section: Pd-1 Inhibits the Functions Of Cd8 1 T Cells In Nsclc Patientsmentioning

confidence: 99%

“…5 Increasing evidence demonstrates that upregulation of the PD-1 inhibitory receptor mediates HIV-specific CD8 1 T-cell functional exhaustion and CD8 1 T cell is apoptosis-sensitive, resulting in an impairment of CD8 1 T cell's ability to control virus replication. [6][7][8][9] Involvement of the PD-1 pathway has also been shown during hepatitis B and C virus infection [10][11][12][13] with PD-L1 expression demonstrated in situ on a wide variety of solid tumors including pancreas, lung, ovarian and bladder tumors. [14][15][16][17][18] Studies relating PD-L1 expression on tumors to disease outcome show that PD-L1 expression strongly correlates with unfavorable prognosis in kidney, bladder, gastric and pancreatic cancer.…”

Section: Introductionmentioning

confidence: 97%

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Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

et al. 2010

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T-cell tolerance is an important mechanism for tumor escape, but the molecular pathways involved in T-cell tolerance remain poorly understood. It remains unknown whether the inhibitory immunoreceptor programmed death-1 (PD-1) plays a role in conditions of human non-small cell lung cancer (NSCLC). In this study, we detected PD-1 expression on CD8 1 T cells from healthy control peripheral blood mononuclear cells (PBMCs) and the PBMCs of NSCLC patients as well as NSCLC tissues. Results showed that tumor-infiltrating CD8 1 T cells had increased PD-1 expression and impaired immune function, including reducing cytokine production capability and impairing capacity to proliferate. Blockade of the PD-1/PD-L1 pathway by the PD-L1-specific antibody partially restored cytokine production and cell proliferation. These data provide direct evidence that the PD-1/PD-L1 pathway is involved in CD8 1 T-cell dysfunction in NSCLC patients. Moreover, blocking this pathway provides a potential therapy target in lung cancer.

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Section: Discussionsupporting

confidence: 91%

Section: Pd-1 Inhibits the Functions Of Cd8 1 T Cells In Nsclc Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

et al. 2010

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“…81 The correlations between PD-1 expression and clinical outcome were recently strengthened by the finding that long-term HIV nonprogressors exhibited functional HIV-specific memory CD8ϩ T cells with markedly lower PD-1 expression, whereas typical progressors showed upregulated PD-1 expression correlating with a reduction in CD4 T-cell number and increased plasma viral load. 82 Furthermore, PD-1 upregulation was associated with reduced perforin and interferon-gamma production, as well as decreased HIV-specific effector memory CD8ϩ T-cell proliferation in progressors. Blockade of this pathway reinvigorates the exhausted T cells, allowing them to expand and produce effector cytokines and reduce viral load.…”

Section: Co-stimulatory Blockade In Eae: An Animal Model Of Msmentioning

confidence: 96%

“…Blockade of this pathway reinvigorates the exhausted T cells, allowing them to expand and produce effector cytokines and reduce viral load. [82][83][84][85] Given the essential role of co-stimulation in the activation of pathogenic T cells, the development of therapeutic strategies aiming at the selective blockade of costimulatory molecules has been a focal point of studies of autoimmune diseases. Blockade of co-stimulation would in fact have the advantage of targeting those T cells that have already received the first signal regardless of the specific antigen triggering the TCR.…”

Section: Co-stimulatory Blockade In Eae: An Animal Model Of Msmentioning

confidence: 99%

Modulating Co-Stimulation

Viglietta

Khoury

2007

Neurotherapeutics

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Summary:The modulation of co-stimulatory pathways represents a novel therapeutic strategy to regulate autoimmune diseases. Auto-reactive CD4ϩ T cells play a critical role in initiating the immune response leading to inflammation and autoimmune diseases. Blocking co-stimulatory signals prevents T-cell activation, thus diminishing autoimmune responses and possibly preventing the progression of autoimmune disease. Blockade of several co-stimulatory pathways has been investigated in animal models and has led to clinical trials testing specific blocking agents in humans. In this review we will describe the role of co-stimulatory pathways, primarily the CD28-B7 pathway, in autoimmune diseases, and we will present in vivo and in vitro studies supporting the efficacy of co-stimulation blockade in animal models of autoimmune disease. Finally, we will discuss the clinical therapeutic efficacy of blocking monoclonal antibodies in preventing or reducing autoantigen driven T-cell activation in humans with particular attention to the CD28/B7 pathway. Inhibiting co-stimulatory molecule interactions by using monoclonal antibodies seems to be an original approach to regulate autoimmune diseases in humans.

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Neurocognitive decline in HIV patients is associated with ongoing T‐cell activation in the cerebrospinal fluid

Grauer

Reichelt

Grüneberg

et al. 2015

Ann Clin Transl Neurol

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ObjectiveHIV-associated neurocognitive disorders (HAND) remain a challenge despite combination antiretroviral therapy (cART). Immune cell activation has been implicated to play a major role in the development of HAND.MethodsIn this study, we used multicolor flow cytometry on peripheral blood (PB) and cerebrospinal fluid (CSF) samples to determine the expression of HLA-DR and programmed death-1 (PD-1) on CD4+ and CD8+ T cells in patients with chronic HIV infection. Expression levels were correlated with HI virus load in PB and CSF, classification of HAND and severity of magnetic resonance imaging (MRI) signal abnormalities.ResultsIn a cohort of 86 HIV patients we found that the grade of neurocognitive impairment and the severity of MRI signal abnormalities correlated with decreasing CD4/CD8-ratios and increased frequencies of HLA-DR expressing CD4+ and CD8+ T cells reaching the highest values in the CSF samples. Importantly, HLA-DR upregulation was still detectable in virologically suppressed HIV patients. Further, T-cell subpopulation analysis of 40 HIV patients showed a significant shift from naïve to effector memory (EM) T cells that was negatively correlated with the grade of neurocognitive impairment in the PB samples. Moreover, PD-1 was significantly increased on CD4+ memory T cells with highest levels on EM T cells in HIV patients with mild or severe neurocognitive alterations.InterpretationThe CD4/CD8 ratio, the proportion of EM to naïve T cells and the immune activation profile of CD4+ and CD8+ T cells in PB and CSF might be useful parameters to monitor the efficacy of cART and to identify HIV patients at risk of further neurocognitive deterioration.

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PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors

Cited by 264 publications

References 37 publications

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

Modulating Co-Stimulation

Neurocognitive decline in HIV patients is associated with ongoing T‐cell activation in the cerebrospinal fluid

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