PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2

Carter, Laura; Fouser, Lynette A.; Jussif, Jason; Fitz, Lori; Deng, Bija; Wood, Clive R.; Collins, Mary; Honjo, Tasuku; Freeman, Gordon J.; Carreño, Beatriz M.

doi:10.1002/1521-4141(200203)32:3<634::aid-immu634>3.0.co;2-9

Cited by 602 publications

(439 citation statements)

References 43 publications

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“…28 It has been reported that PD-1 may exert its effects directly by inhibiting early activation events that are positively regulated by CD28 or indirectly through IL-2. 29 In our study, we did not detect upregulation of cytotoxic T lymphocyte-associated antigen 4 or downregulation of CD28 (data not shown) on tumor-infiltrating CD8 1 T cells, so cytotoxic T lymphocyte-associated antigen 4 and CD28 are unlikely to be contributing to the CD8 1 T-cell defects. More likely, PD-1 1 tumor-infiltrating CD8 1 T-cell function was impaired due to decreased IL-2 production upon PD-1 ligation since IL-2 production was indeed lower than PD-1 low CD8 1 T cells in our system.…”

Section: Discussionmentioning

confidence: 47%

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: Discussionmentioning

confidence: 47%

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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“…Recent reports propose that PD-1-mediated inhibition could be overcome by CD28 costimulation or IL-2 production [19,28]. The high levels of CD86 expression that we observed on the DC-1 subset suggest that PD-1-B7-H1/B7-DC-mediated inhibition might be overridden by CD28-CD86 costimulation in the CD86 high DC.…”

Section: Discussionmentioning

confidence: 48%

Preferential contribution of B7‐H1 to programmed death‐1‐mediated regulation of hapten‐specific allergic inflammatory responses

et al. 2003

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Programmed death-1 (PD-1) and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, are new CD28-B7 family members that may be involved in the regulation of immune responses. We examined the roles of these molecules in mouse hapten-induced contact hypersensitivity (CH). Administration of anti-PD-1 mAb at sensitization significantly enhanced and prolonged ear swelling. Treatment with anti-B7-H1 mAb, but not anti-B7-DC mAb, also enhanced CH reactions. The anti-PD-1 mAb treatment at sensitization significantly increased the T cell number of draining lymph nodes (DLN). B7-H1 was induced on activated T cells and antigen-presenting cells (APC) in the skin and the DLN, whereas B7-DC expression was restricted to dendritic cells (DC) in the dermis and the DLN. A particular subset of DC, B7-H1 + B7-DC -CD86 low , was found in sensitized DLN. The blockade of B7-H1, but not B7-DC, dramatically enhanced the initial T cell proliferative responses against hapten-pulsed DLN APC, suggesting the preferential contribution of B7-H1 to the T cell-APC interaction. Our results demonstrate the regulatory role of PD-1 and the differential roles of B7-H1 and B7-DC in hapten-induced immune responses. The PD-1-B7-H1 pathway may play a unique role in regulating inflammatory responses.

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“…PD-1 expression in viremic subjects was Ͼ2-fold higher on the HIVspecific CD4 ϩ than CD8 ϩ T cells (25). In subjects whose viral loads were suppressed using ART, PD-1 expression on HIV-specific CD4 ϩ T cells decreased by 50% to similar levels as CMVspecific or SEB-reactive CD4 ϩ T cells while it dropped by only 20% on Gag-specific CD8 ϩ T cells.…”

Section: Discussionmentioning

confidence: 91%

Programmed Death 1 Expression on HIV-Specific CD4+ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction

D'Souza¹,

Fontenot

Mack³

et al. 2007

The Journal of Immunology

224

207

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Functional impairment of HIV-specific CD4+ T cells during chronic HIV infection is closely linked to viral replication and thought to be due to T cell exhaustion. Programmed death 1 (PD-1) has been linked to T cell dysfunction in chronic viral infections, and blockade of the PD-1 pathway restores HIV-specific CD4+ and CD8+ T cell function in HIV infection. This study extends those findings by directly examining PD-1 expression on virus-specific CD4+ T cells. To investigate the role of PD-1 in HIV-associated CD4+ T cell dysfunction, we measured PD-1 expression on blood and lymph node T cells from HIV-infected subjects with chronic disease. PD-1 expression was significantly higher on IFN-γ-producing HIV-specific CD4+ T cells compared with total or CMV-specific CD4+ T cells in untreated HIV-infected subjects (p = 0.0001 and p < 0.0001, respectively). PD-1 expression on HIV-specific CD4+ T cells from subjects receiving antiretroviral therapy was significantly reduced (p = 0.007), and there was a direct correlation between PD-1 expression on HIV-specific CD4+ T cells and plasma viral load (r = 0.71; p = 0.005). PD-1 expression was significantly higher on HIV-specific T cells in the lymph node, the main site of HIV replication, compared with those in the blood (p = 0.0078). Thus, PD-1 expression on HIV-specific CD4+ T cells is driven by persistent HIV replication, providing a potential target for enhancing the functional capacity of HIV-specific CD4+ T cells.

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PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2

Cited by 602 publications

References 43 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

Preferential contribution of B7‐H1 to programmed death‐1‐mediated regulation of hapten‐specific allergic inflammatory responses

Programmed Death 1 Expression on HIV-Specific CD4+ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction

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