The risks of targeting co-inhibitory pathways to modulate pathogen-directed T cell responses

Frebel, Helge; Oxenius, Annette

doi:10.1016/j.it.2012.12.002

Cited by 18 publications

(17 citation statements)

References 80 publications

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“…In this way, PD-1 acts as a safeguard against prolonged and potentially detrimental activation (5–7). During GVHD, PD-1 expression on alloreactive T cells limits the severity of GVHD and lack of PD-1 signaling drives T cell expansion, increases IFN-γ production, and accelerates GVHD onset (18).…”

Section: Discussionmentioning

confidence: 99%

“…Of particular interest, blockade of the PD-1 pathway is being used to increase anti-tumor immunity in patients with advanced stage cancers (4, 11, 13). However, augmenting T cell responses via PD-1 inhibition may have unintended consequences including devastating immune reactions to routine infections (4, 5, 14, 15) and an increased prevalence of autoimmunity (6, 7, 16, 17). In graft-versus-host disease (GVHD), it is well known that absence of PD-1 signaling results in increased IFN-gamma production and lethal immunopathology (18), likely through increased alloreactive T cell expansion and heightened Th1 differentiation (19).…”

Section: Introductionmentioning

confidence: 99%

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Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism

Tkachev

Goodell

Opipari

et al. 2015

The Journal of Immunology

101

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The co-inhibitory receptor programmed death-1 (PD-1) maintains immune homeostasis by negatively regulating T cell function and survival. Blockade of PD-1 increases the severity of graft-versus-host disease (GVHD), but the interplay between PD-1 inhibition and T cell metabolism is not well studied. We found that both murine and human alloreactive T cells concomitantly up-regulated PD-1 expression and increased levels of reactive oxygen species (ROS) following allogeneic bone marrow transplantation. This PD-1HiROSHi phenotype was specific to alloreactive T cells and was not observed in syngeneic T cells during homeostatic proliferation. Blockade of PD-1 signaling decreased both mitochondrial H2O2 and total cellular ROS levels and PD-1 driven increases in ROS were dependent upon the oxidation of fatty acids, as treatment with etomoxir nullified changes in ROS levels following PD-1 blockade. Downstream of PD-1, elevated ROS levels impaired T cell survival in a process reversed by anti-oxidants. Furthermore, PD-1 driven changes in ROS were fundamental to establishing a cell’s susceptibility to subsequent metabolic inhibition, as blockade of PD-1 decreased the efficacy of later F1F0-ATP synthase modulation. These data indicate that PD-1 facilitates apoptosis in alloreactive T cells by increasing reactive oxygen species in a process dependent upon the oxidation of fat. In addition, blockade of PD-1 undermines the potential for subsequent metabolic inhibition, an important consideration given the increasing use of anti-PD-1 therapies in the clinic.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism

Tkachev

Goodell

Opipari

et al. 2015

The Journal of Immunology

101

View full text Add to dashboard Cite

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“…In T-cells, this well-known process is mediated by inhibitory receptors such as PD-1 or CTLA-4 (57), pathways that have also been described and contribute to reduced T-cell responsiveness in malaria infection (20, 58). Importantly, negative immune regulation of T-cells not only leads to what is described as “exhaustion”, but is an important factor in preventing immune pathology (59) and in mediating contraction of immune responses when a pathogen is cleared (60). In analogy, temporary induction of FcRL4 on activated B-cells across all B-cell subsets following malaria infection may be a physiological response and simply serve to bring these cells back to the steady state.…”

Section: Discussionmentioning

confidence: 99%

BAFF and BAFF Receptor Levels Correlate with B Cell Subset Activation and Redistribution in Controlled Human Malaria Infection

Scholzen

Teirlinck

Bijker

et al. 2014

The Journal of Immunology

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Characteristic features of Plasmodium falciparum malaria are polyclonal B-cell activation and an altered composition of the blood B-cell compartment, including expansion of CD21−CD27− atypical memory B-cells. B-cell activating factor (BAFF) is a key cytokine in B-cell homeostasis, but its potential contribution to the modulation of the blood B-cell pool during malaria remains elusive. In the controlled human malaria model (CHMI) in malaria-naïve Dutch volunteers, we therefore examined the dynamics of BAFF induction and B-cell subset activation and composition, to investigate whether these changes are linked to malaria-induced immune activation and in particular induction of BAFF. Alterations in B-cell composition after CHMI closely resembled those observed in endemic areas. We further found distinct kinetics of proliferation for individual B-cell subsets across all developmental stages. Proliferation peaked either immediately after blood-stage infection or at convalescence, and for most subsets was directly associated with the peak parasitemia. Concomitantly, plasma BAFF levels during CHMI were increased and correlated with membrane-expressed BAFF on monocytes and dendritic cells, as well as blood-stage parasitemia and parasite-induced IFNγ. Correlating with elevated plasma BAFF and IFNγ levels, IgD−CD38lowCD21−CD27− atypical B-cells showed the strongest proliferative response of all memory B-cell subsets. This provides unique evidence for a link between malaria-induced immune activation and temporary expansion of this B-cell subset. Finally, baseline BAFF-receptor levels prior to CHMI were predictive of subsequent changes in proportions of individual B-cell subsets. These findings suggest an important role of BAFF in facilitating B-cell subset proliferation and redistribution as a consequence of malaria-induced immune activation.

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“…Although blocking inhibitory receptors can have significant impacts on improving cellular immune responses, adverse effects can also occur (Frebel and Oxenius, 2013). These can result from immunopathology caused by enhanced T cell responses, which does develop if PD-1 treatment is applied early during the course of chronic LCMV infection.…”

Section: Preventing and Reversing T Cell Exhaustionmentioning

confidence: 99%

T cell exhaustion during persistent viral infections

2015

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Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control.

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The risks of targeting co-inhibitory pathways to modulate pathogen-directed T cell responses

Cited by 18 publications

References 80 publications

Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism

Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism

BAFF and BAFF Receptor Levels Correlate with B Cell Subset Activation and Redistribution in Controlled Human Malaria Infection

T cell exhaustion during persistent viral infections

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