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

D'Souza, Michelle; Fontenot, Andrew P.; Mack, Doug G.; Lozupone, Catherine; Dillon, Stephanie M.; Meditz, Amie L.; Wilson, Cara C.; Connick, Elizabeth; Palmer, Brent E.

doi:10.4049/jimmunol.179.3.1979

Cited by 222 publications

(219 citation statements)

References 34 publications

(46 reference statements)

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“…Thus, little information exists on the expression of PD-1 on Ag-specific CD4 ϩ T cells in a target organ. We have recently shown that PD-1 expression on CD4 ϩ T cells in the lymph nodes of subjects with chronic HIV infection was significantly higher than on cells from blood (7). Although this is in part a consequence of persistently high levels of viral Ag, it may also be that PD-1 expression in target organs is higher than in the bloodstream because of the activated state of the cells.…”

Section: Discussionmentioning

confidence: 82%

“…CD4 ϩ T cells from a target organ. During chronic HIV infection, it has recently been shown that PD-1 is up-regulated on CD4 ϩ T cells to a greater extent in the lymph node (i.e., the target organ in HIV disease) compared with peripheral blood (7). We examined the expression of PD-1 on beryllium-specific CD4 ϩ T cells from the blood and BAL of beryllium-sensitized (BeS) and CBD subjects.…”

Section: Up-regulation Of Programmed Death-1 Expression Onmentioning

confidence: 99%

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Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease

Palmer¹,

Mack²,

Martin³

et al. 2008

The Journal of Immunology

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Chronic beryllium disease (CBD) is caused by workplace exposure to beryllium and is characterized by the accumulation of memory CD4+ T cells in the lung. These cells respond vigorously to beryllium salts in culture by producing proinflammatory Th1-type cytokines. The presence of these inflammatory cytokines leads to the recruitment of alveolar macrophages, alveolitis, and subsequent granuloma development. It has been shown that chronic exposure to conventional Ags leads to up-regulation in the expression of negative regulators of T cells such as programmed death-1 (PD-1). Due to the persistence of beryllium in the lung after the cessation of exposure, aberrant regulation of the PD-1 pathway may play an important role in CBD development. In the present study, PD-1 expression was measured on blood and bronchoalveolar lavage (BAL) CD4+ T cells from beryllium-sensitized and CBD subjects. PD-1 expression was significantly higher on BAL CD4+ T cells compared with those cells in blood, with the highest expression on the beryllium-specific T cell subset. In addition, the expression of PD-1 on BAL CD4+ T cells directly correlated with the severity of the T cell alveolitis. Increased expression of the PD-1 ligands, PD-L1 and PD-L2, on BAL CD14+ cells compared with blood was also seen. The addition of anti-PD-1 ligand mAbs augmented beryllium-induced CD4+ T cell proliferation, and an inverse correlation was seen between PD-1 expression on beryllium-specific CD4+ T cells and beryllium-induced proliferation. Thus, the PD-1 pathway is active in beryllium-induced disease and plays a key role in controlling beryllium-induced T cell proliferation.

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Section: Discussionmentioning

confidence: 82%

Section: Up-regulation Of Programmed Death-1 Expression Onmentioning

confidence: 99%

Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease

Palmer¹,

Mack²,

Martin³

et al. 2008

The Journal of Immunology

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“…16 Thus, IFNg single production may be a sign of functional exhaustion of virus-specific T-cells during chronic viral infection, as has been reported in several other studies. 2,[35][36][37] In light of our data, many studies that have focused on measuring single cytokines and chose IFNg would not have been able to differentiate an inefficient single IFNg response from an efficient master response. 14,15,38 A similar limitation applies to a report by Bunde et al, 39 who reported no correlation between pp65-stimulated CD8 þ T-cells and protection, whereas IE-1 stimulated CD8 þ Tcells correlated with protection.…”

Section: Discussionmentioning

confidence: 95%

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

Krol

Stuchlý

Hubáček

et al. 2010

Bone Marrow Transplant

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Depletion of cellular immunity as a consequence of conditioning before allogeneic hematopoietic SCT (HSCT) frequently results in CMV reactivation, which may in turn lead to life-threatening infections and require timely antiviral treatment. We have investigated the functional signatures of CMV-specific CD4 þ and CD8 þ T-cells in 191 samples from 118 individuals. We compared healthy donors with both patients with high and undetectable viral loads, and those who controlled and did not control their CMV reactivations. Polychromatic flowcytometric measurements of CD154 (CD40L), intracellular cytokines (IFNc, IL2) and a degranulation marker (CD107a) allowed us to assess the functional status of various T-cells simultaneously. We found that dual IFNc/ IL2-producing CD8 þ T-cells were present in patients controlling their CMV reactivations but absent from noncontrollers. CD8 þ T-cells that produce only IFNc were the most abundant subtype, but they most likely represent non-protective memory cells. Distinct functional signatures were examined by hierarchical clustering, and this revealed that, unlike polyfunctional CD8 þ T-cells, CD8 þ T-cells that produce IFNc alone were not functioning in concert with other subsets. In conclusion, our study revealed functional signatures that may be useful for immune monitoring, and it could change the interpretation of previous studies that assessed only IFNc.

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“…PBMCs and BAL cells were stimulated, washed, incubated with FcR-blocking reagent (Miltenyi Biotec, Bergisch Gladbach, Germany), stained, and analyzed as detailed in the online supplement. In certain experiments, PBMCs and BAL cells were labeled with Celltrace Violet (Life Technologies, Carlsbad, CA) as previously described (12,19), and HIV-1 gag-specific T-cell proliferation was determined as detailed in the online supplement.…”

Section: Methods Study Populationmentioning

confidence: 99%

Lymphocytic Alveolitis Is Associated with the Accumulation of Functionally Impaired HIV-Specific T Cells in the Lung of Antiretroviral Therapy–Naive Subjects

Neff¹,

Chain²,

MaWhinney³

et al. 2015

Am J Respir Crit Care Med

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Rationale: Lymphocytic alveolitis in HIV-1-infected individuals is associated with multiple pulmonary complications and a poor prognosis. Although lymphocytic alveolitis has been associated with viremia and an increased number of CD8 1 T cells in the lung, its exact cause is unknown.Objectives: To determine if HIV-1-specific T cells are associated with lymphocytic alveolitis in HIV-1-infected individuals.Methods: Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and untreated HIV-1-infected individuals, we examined the frequency and functional capacity of HIV-1-specific T cells. Measurements and Main Results:We found that HIV-1-specific T cells were significantly elevated in the BAL compared with blood of HIV-1-infected individuals and strongly correlated with T-cell alveolitis. Expression of Ki67, a marker of in vivo proliferation, was significantly reduced on HIV-1-specific T cells in BAL compared with blood, suggesting a diminished proliferative capacity. In addition, HIV-1-specific CD4 1 and CD8 1 T cells in BAL had higher expression of programmed death 1 (PD-1) and lower cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression than those in the blood. A strong correlation between PD-1, but not CTLA-4, and HIV-1-specific T-cell proliferation was seen, and blockade of the PD-1/PD-L1 pathway augmented HIV-1-specific T-cell proliferation, suggesting that the PD-1 pathway was the main cause of reduced proliferation in the lung.Conclusions: These findings suggest that alveolitis associated with HIV-1 infection is caused by the recruitment of HIV-1-specific CD4 1 and CD8 1 T cells to the lung. These antigen-specific T cells display an impaired proliferative capacity that is caused by increased expression of PD-1.

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

Cited by 222 publications

References 34 publications

Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease

Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

Lymphocytic Alveolitis Is Associated with the Accumulation of Functionally Impaired HIV-Specific T Cells in the Lung of Antiretroviral Therapy–Naive Subjects

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