Notch signaling regulates PD‐1 expression during CD8<sup>+</sup> T‐cell activation

Mathieu, Mélissa; Cotta-Grand, Natacha; Daudelin, Jean-François; Thébault, Paméla; Labrecque, Nathalie

doi:10.1038/icb.2012.53

Cited by 114 publications

(78 citation statements)

References 33 publications

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“…Unlike what would have been expected from in vitro studies (22,23,37), ablation of Notch1 and Notch2 receptor expression did not decrease the in vivo proliferation of CD8 + T cells. This difference might be the result of unspecific effect of the Notch inhibitors that were used for the in vitro studies.…”

Section: Discussioncontrasting

confidence: 43%

“…It was shown by us and others that CD8 + T cells upregulate Notch1 and Notch2 expression following TCR stimulation (22,24,37,38). However, Notch3 and Notch4 mRNA were not increased (24,39) (data not shown); thus, the deletion of Notch1 and Notch2 genes should completely abrogate Notch signaling in CD8 + T cells.…”

Section: Notch Signaling Controls Slec Differentiationmentioning

confidence: 97%

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The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

Mathieu

Duval

Daudelin

et al. 2015

The Journal of Immunology

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Following an infection, naive CD8+ T cells expand and differentiate into two main populations of effectors: short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). There is limited understanding of the molecular mechanism and cellular processes governing this cell fate. Notch is a key regulator of cell fate decision relevant in many immunological pathways. In this study, we add to the role of Notch in cell fate decision and demonstrate that the Notch signaling pathway controls the MPEC/SLEC differentiation choice following both Listeria infection and dendritic cell immunization of mice. Although fewer SLECs were generated, Notch deficiency did not alter the rate of memory CD8+ T cell generation. Moreover, we reveal that the Notch signaling pathway plays a context-dependent role for optimal cytokine production by effector CD8+ T cells. Together, our results unravel critical functions for the Notch signaling pathway during effector CD8+ T cell differentiation.

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Section: Discussioncontrasting

confidence: 43%

Section: Notch Signaling Controls Slec Differentiationmentioning

confidence: 97%

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

Mathieu

Duval

Daudelin

et al. 2015

The Journal of Immunology

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“…PD-1 expression is activated by NFATc1 (nuclear factor of activated T cells c1), AP-1, NF-B, and Notch (25,74,75). Therefore, inactivation of these transcription factors would reduce PD-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

2015

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Myeloid-derived suppressor cells (MDSCs) were recently found to accumulate in the lungs during Pneumocystis pneumonia (PcP). Adoptive transfer of these cells caused lung damage in recipient mice, suggesting that MDSC accumulation is a mechanism of pathogenesis in PcP. In this study, the phagocytic activity of alveolar macrophages (AMs) was found to decrease by 40% when they were incubated with MDSCs from Pneumocystis-infected mice compared to those incubated with Gr-1 ؉ cells from the bone marrow of uninfected mice. The expression of the PU.1 gene in AMs incubated with MDSCs also was decreased. This PU.1 downregulation was due mainly to decreased histone 3 acetylation and increased DNA methylation caused by MDSCs. MDSCs were found to express high levels of PD-L1, and alveolar macrophages (AMs) were found to express high levels of PD-1 during PcP. Furthermore, PD-1 expression in AMs from uninfected mice was increased by 18-fold when they were incubated with MDSCs compared to those incubated with Gr-1 ؉ cells from the bone marrow of uninfected mice. The adverse effects of MDSCs on AMs were diminished when the MDSCs were pretreated with anti-PD-L1 antibody, suggesting that MDSCs disable AMs through PD-1/PD-L1 ligation during PcP.

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“…Pdcd1 expression can be positively and negatively regulated by different transcription factors such as nuclear factor of activated T cells (NFAT), Forkhead box protein O1 (FoxO1), Notch, activator protein 1 (AP1), and B-lymphocyte maturation protein 1 (Blimp1; refs. [16][17][18][19]. Despite this, the identity of the upstream signaling event(s) that control PD-1 expression has been unclear.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Inhibition of PD-1 Transcription Is an Effective Alternative to Antibody Blockade in Cancer Therapy

2018

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The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase, GSK-3a/b, is a central regulator of PD-1 transcription in CD8 þ T cells. Here, we show that the use of smallmolecule inhibitors of GSK-3a/b (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PD-L1-blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Furthermore, the conditional genetic deletion of GSK-3a/b reduced PD-1 expression on CD8 þ T cells and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor-infiltrating lymphocytes, while increasing Tbx21 (T-bet) transcription, and the expression of CD107a þ (LAMP1) and granzyme B (GZMB) on CD8 þ T cells. Finally, the adoptive transfer of T cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pretreatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8 þ T-cell function in cancer therapy to a similar degree as PD-1-blocking antibodies.Significance: These findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8þ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies, offering a next-generation approach in the design of immunotherapeutic approaches for cancer management. Cancer Res; 78(3); 706-17.Ó2017 AACR.

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Notch signaling regulates PD‐1 expression during CD8⁺ T‐cell activation

Cited by 114 publications

References 33 publications

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

Small-Molecule Inhibition of PD-1 Transcription Is an Effective Alternative to Antibody Blockade in Cancer Therapy

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Notch signaling regulates PD‐1 expression during CD8+ T‐cell activation

Cited by 114 publications

References 33 publications

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

Small-Molecule Inhibition of PD-1 Transcription Is an Effective Alternative to Antibody Blockade in Cancer Therapy

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Notch signaling regulates PD‐1 expression during CD8⁺ T‐cell activation