B7-H1 (PD-L1) on T cells is required for T-cell-mediated conditioning of dendritic cell maturation

Talay, Oezcan; Shen, Ching Hung; Chen, Lieping; Chen, Jianzhu

doi:10.1073/pnas.0813367106

Cited by 67 publications

(50 citation statements)

References 29 publications

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“…This may compensate for the lower PD-1 expression, ultimately yielding a balance in overall cellular activation. As CRC − mice had fewer T SLEC compared to WT, it is possible that early, optimal PD-1 expression may be required to coordinate an effective immune response, as has been previously reported (51), rather than acting as a cellular inhibitor as occurs during chronic stimulation. The decrease in effector CD8 T cells and/or function may be mediated through a number of mechanisms.…”

Section: Discussionmentioning

confidence: 78%

Conserved Region C Functions To Regulate PD-1 Expression and Subsequent CD8 T Cell Memory

Bally

Tang

Lee

et al. 2017

The Journal of Immunology

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Expression of programmed death 1 (PD-1) on CD8 T cells promotes T cell exhaustion during chronic antigen exposure. During acute infections, PD-1 is transiently expressed and has the potential to modulate CD8 T cell memory formation. Conserved Region C (CR-C), a promoter proximal cis-regulatory element that is critical to PD-1 expression in vitro, responds to NFATc1, FoxO1, and/or NF-κB signaling pathways. Here, a CR-C knockout mouse (CRC−) was established to determine its role on PD-1 expression and corresponding effects on T cell function in vivo. Deletion of CR-C decreased PD-1 expression on CD4 T cells and antigen-specific CD8 T cells during acute and chronic lymphocytic choriomeningitis virus (LCMV) challenges, but did not affect the ability to clear an infection. Following acute LCMV infection, memory CD8 T cells in the CRC− mouse were formed in greater numbers, were more functional, and were more effective at responding to a melanoma tumor than wild-type memory cells. These data implicate a critical role for CR-C in governing PD-1 expression, and a subsequent role in guiding CD8 T cell differentiation. The data suggest the possibility that titrating PD-1 expression during CD8 T cell activation could have important ramifications in vaccine development and clinical care.

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Section: Discussionmentioning

confidence: 78%

Conserved Region C Functions To Regulate PD-1 Expression and Subsequent CD8 T Cell Memory

Bally

Tang

Lee

et al. 2017

The Journal of Immunology

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“…Our study adds that PD-1/PDL-1 regulation of CD8 T cell effector function is mediated locally by the epithelial cells of the lung, is regulated by IFNAR signaling, and can be therapeutically manipulated in the airways by intranasal administration of anti-PDL-1 blocking antibodies. Since PD-1 signaling has been shown to impact dendritic cell maturation, antigen presentation, and T cell priming and expansion (34,(42)(43)(44), it is important to differentiate the systemic role of PD-1/ PDL-1 during the generation of adaptive immune responses from the specific role at the mucosal site of infection during epithelial-T cell interaction cross talk.…”

Section: Discussionmentioning

confidence: 99%

Local Blockade of Epithelial PDL-1 in the Airways Enhances T Cell Function and Viral Clearance during Influenza Virus Infection

McNally

Willette

et al. 2013

J Virol

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“…Although this Fc-mediated effect is in fact required for the efficacy of some immunotherapeutic antibodies (14), it may in part be counterproductive in the case of this receptor-ligand pair. Both PD-1 and PD-L1 are expressed on the surface of antitumor cytotoxic T cells (15,16), and as such, antibodies targeting PD-1 and PD-L1 may paradoxically result in the undesirable depletion of the very lymphocytes they are intended to activate. Consistent with this hypothesis, treatment with anti-PD-1 antibodies of anti-PD-1 antibodies has been reported to correlate with lower circulating T-cell numbers in patients (17).…”

Section: Significancementioning

confidence: 99%

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging

Maute

Gordon

Mayer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

310

314

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Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells. To determine if PD-1:PD-L1-directed immunotherapy could be improved with smaller, nonantibody therapeutics, we used directed evolution by yeast-surface display to engineer the PD-1 ectodomain as a high-affinity (110 pM) competitive antagonist of PD-L1. In contrast to anti-PD-L1 monoclonal antibodies, high-affinity PD-1 demonstrated superior tumor penetration without inducing depletion of peripheral effector T cells. Consistent with these advantages, in syngeneic CT26 tumor models, high-affinity PD-1 was effective in treating both small (50 mm 3 ) and large tumors (150 mm 3 ), whereas the activity of anti-PD-L1 antibodies was completely abrogated against large tumors. Furthermore, we found that high-affinity PD-1 could be radiolabeled and applied as a PET imaging tracer to efficiently distinguish between PD-L1-positive and PD-L1-negative tumors in living mice, providing an alternative to invasive biopsy and histological analysis. These results thus highlight the favorable pharmacology of small, nonantibody therapeutics for enhanced cancer immunotherapy and immune diagnostics.protein engineering | cancer immunotherapy | PET imaging | PD-1 | PD-L1

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B7-H1 (PD-L1) on T cells is required for T-cell-mediated conditioning of dendritic cell maturation

Cited by 67 publications

References 29 publications

Conserved Region C Functions To Regulate PD-1 Expression and Subsequent CD8 T Cell Memory

Conserved Region C Functions To Regulate PD-1 Expression and Subsequent CD8 T Cell Memory

Local Blockade of Epithelial PDL-1 in the Airways Enhances T Cell Function and Viral Clearance during Influenza Virus Infection

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging

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