PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis

Zinselmeyer, Bernd H.; Heydari, Sara; Sacristán, Catarina; Nayak, Debasis; Cammer, Michael; Herz, Jasmin; Cheng, Xiaoxiao; Davis, Simon J.; Dustin, Michael L.; McGavern, Dorian B.

doi:10.1084/jem.20121416

Cited by 215 publications

(220 citation statements)

References 73 publications

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“…In contrast, Ruocco and colleagues (16) concluded that a-CTLA-4 antibodies fail to generate protective tumor immunity and must be combined with radiation because anti-CTLA-4 treatment increases T-cell motility. Unlike these earlier reports, our findings are more consistent with the conclusion that the antibodies mediate their positive effects on tumor immunity by blocking CTLA-4-mediated inhibition and enhancing T-cell motility in tumors, similar to the reversal of the exhausted T-cell motility paralysis during chronic viral infections (18).…”

Section: Discussionsupporting

confidence: 90%

“…This conclusion is in direct opposition to the current model of CTLA-4-mediated inhibition via the reversal of the TCR-induced stop signal (17). Instead, our observations resemble the recently described reversal of the antiviral T-cell motility paralysis by PD-1-specific antibodies during T-cell exhaustion in persistent viral infections (18).…”

Section: Introductioncontrasting

confidence: 99%

“…Inoculation of mice with the clone 13 variant of lymphocytic choriomeningitis virus (LCMV), which establishes a chronic viral infection due to immune-cell exhaustion, causes "motility paralysis" of virus-specific CD4 þ and CD8 þ T cells. This paralysis is manifested by decreased T-cell velocities in clone 13-infected mice relative to mice infected with the Armstrong strain of LCMV, which is cleared by virus-specific T cells (18). This phenomenon resembles the lower motility of pmel-1 T cells in progressively growing GVax-treated tumors relative to their velocities in tumors treated with the effective combination therapy in our system.…”

Section: Discussionmentioning

confidence: 57%

“…This phenomenon resembles the lower motility of pmel-1 T cells in progressively growing GVax-treated tumors relative to their velocities in tumors treated with the effective combination therapy in our system. Similar to the effects of a-CTLA-4 antibodies in our protective immunotherapy regimen, the antiviral T-cell paralysis can be reversed by blocking antibodies to PD-1 and PD-L1, both of which have been previously shown to treat persistent viral infections in mice and humans by restoring function to exhausted T cells (18).…”

Section: Discussionmentioning

confidence: 88%

“…The idea that antibodies blocking inhibitory molecules can have differential effects on T-cell motility, depending on the immune context, is supported by a study showing that a-PD-1 and a-PD-L1 antibodies improve antiviral T-cell motility and lead to viral clearance in a mouse model of persistent viral infection (18). Inoculation of mice with the clone 13 variant of lymphocytic choriomeningitis virus (LCMV), which establishes a chronic viral infection due to immune-cell exhaustion, causes "motility paralysis" of virus-specific CD4 þ and CD8 þ T cells.…”

Section: Discussionmentioning

confidence: 99%

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Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Pentcheva-Hoang

Simpson

Montalvo-Ortiz

et al. 2014

Cancer Immunology Research

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It is now clear that anti-CTLA-4 (a-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-cell function or by depletion of regulatory T cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T cells, thus interrupting T-cell receptor signaling and subsequent T-cell activation. We examined the behavior of melanoma-specific CD8 þ pmel-1 T cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included a-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-cell motility. When a-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T cells in tumor-draining lymph nodes also increased. Because a-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-cell motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T cells and tumor targets or antigen-presenting cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-cell motility paralysis by programmed death 1 (PD-1)-specific antibodies during T-cell exhaustion in persistent viral infections. Cancer Immunol Res; 2(10); 970-80. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 90%

Section: Introductioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Pentcheva-Hoang

Simpson

Montalvo-Ortiz

et al. 2014

Cancer Immunology Research

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Microbial pathogenesis revealed by intravital microscopy: pros, cons and cautions

Stolp

Melican

2016

FEBS Letters

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Intravital multiphoton imaging allows visualization of infections and pathogenic mechanisms within intact organs in their physiological context. Today, most organs of mice and rats are applicable to in vivo or ex vivo imaging, opening completely new avenues for many researchers. Advances in fluorescent labeling of pathogens and infected cells, as well as improved small animal models for human pathogens, led to the increased application of in vivo imaging in infectious diseases research in recent years. Here, we review the latest literature on intravital or ex vivo imaging of viral and bacterial infections and critically discuss requirements, benefits and drawbacks of applied animal models, labeling strategies, and imaged organs.

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PD‐1‐induced T cell exhaustion is controlled by a Drp1‐dependent mechanism

et al. 2021

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Programmed cell death‐1 (PD‐1) signaling downregulates the T‐cell response, promoting an exhausted state in tumor‐infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin‐related protein‐1 (Drp1)‐dependent mitochondrial fission plays a crucial role in sustaining T‐cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD‐1 in tumor‐infiltrating T cells. Here, we show that PD‐1 pos CD8 + T cells infiltrating an MC38 (murine adenocarcinoma)‐derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD‐1 neg counterparts. Also, PD‐1 pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD‐1 signaling directly prevents mitochondrial fragmentation following T‐cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor‐infiltrating PD‐1 pos CD8 + T cells seems to be a mechanism exploited by PD‐1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor‐infiltrating T cells may become a valuable target to ameliorate the anticancer immune response in future immunotherapy approaches.

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PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis

Abstract: PD-L1 decreases anti-viral CD8+ T cell motility and PD-1 blockade restores motility in the presence of high viral loads.

Cited by 215 publications

References 73 publications

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Microbial pathogenesis revealed by intravital microscopy: pros, cons and cautions

PD‐1‐induced T cell exhaustion is controlled by a Drp1‐dependent mechanism

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