The chronicles of T-cell exhaustion

Kaech, Susan M.

doi:10.1038/nature21508

Cited by 26 publications

(21 citation statements)

References 12 publications

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“…Myriad factors may contribute to this failure, but one key factor is that after prolonged antigenic exposure, the responses of effector T cells may gradually attenuate. This phenomenon is called T cell exhaustion[6, 7, 8], and is characterized by reduced production of IFN-γ and increased expression of multiple inhibitory receptors, notably PD-1. These observations among others ultimately led to the development of PD-1:PD-L1 pathway blockade as a therapeutic anti-cancer strategy.…”

Section: Brief Review Of Immunology For Non-immunologistsmentioning

confidence: 99%

Atezolizumab for the treatment of non-small cell lung cancer

Santini

Rudin

2017

Expert Review of Clinical Pharmacology

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Introduction The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1). Areas Covered This drug profile article covers the basics of the cancer-immunity cycle and reviews some aspects of innate and adaptive immunology. We discuss the discovery of PD-L1 and PD-L2 while highlight the potential differences in targeting PD-L1 versus PD-1. In addition, we briefly summarized the available pre-clinical and clinical data of atezolizumab use in NSCLC. A special section covers the challenges of PD-L1 immunohistochemistry assay. Expert commentary PD-1:PD-L1 blockade has taken the lead in the immunotherapeutics field and represents the backbone of developing combination immunotherapies. Atezolizumab represents a step forward in the treatment of advanced NSCLC, nonetheless PD1:PD-L1 blockade in early-stage lung cancer is still a matter of debate.

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Section: Brief Review Of Immunology For Non-immunologistsmentioning

confidence: 99%

Atezolizumab for the treatment of non-small cell lung cancer

Santini

Rudin

2017

Expert Review of Clinical Pharmacology

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“…The strength of the signal transduction by the TCR is influenced by the cellular context of Ag recognition. However, the balance between activating and inhibitory signals ensures the development of an effective T cell immune response . In fact, there are several signaling proteins contributing to the active up‐ or down‐regulation during the priming of a T cell immune response .…”

Section: Introductionmentioning

confidence: 99%

“…However, the balance between activating and inhibitory signals ensures the development of an effective T cell immune response . In fact, there are several signaling proteins contributing to the active up‐ or down‐regulation during the priming of a T cell immune response . Programmed cell death protein 1 (PD‐1), a membrane protein that is an inhibitory receptor from the CD28 family, is initially identified as a negative regulator of Th1‐type immunity in humans and mice .…”

Section: Introductionmentioning

confidence: 99%

“…While PD‐1 is not expressed on naïve T cells, it is up‐regulated following TCR‐mediated activation and is readily observed on both activated and exhausted T cells . It shows that PD‐1, like other members of T‐cell inhibitory molecules such as T‐cell immunoglobulin and mucin domain‐containing molecule 3 (Tim‐3) and co‐stimulatory receptor cytotoxic T‐lymphocyte Ag‐4 (CTLA‐4), may represent a negative regulator in T‐cell immune response during chronic infections . PD‐L1 and PD‐L2 are both B7 family members and are currently the only known ligands for PD‐1 .…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10] In fact, there are several signaling proteins contributing to the active up-or down-regulation during the priming of a T cell immune response. 8,11,12 Programmed cell death protein 1 (PD-1), a membrane protein that is an inhibitory receptor from the CD28 family, is initially identified as a negative regulator of Th1-type immunity in humans and mice. 13,14 While PD-1 is not expressed on naïve T cells, it is up-regulated following TCR-mediated activation and is readily observed on both activated and exhausted T cells.…”

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confidence: 99%

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PD-1 modulating Mycobacterium tuberculosis-specific polarized effector memory T cells response in tuberculosis pleurisy

Jin

et al. 2019

Journal of Leukocyte Biology

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Host‐pathogen interactions in tuberculosis (TB) should be studied at the disease sites because Mycobacterium tuberculosis (M.tb) is predominantly contained in local tissue lesions. T‐cell immune responses are required to mount anti‐mycobacterial immunity. However, T‐cell immune responses modulated by programmed cell death protein 1 (PD‐1) during tuberculosis pleurisy (TBP) remains poorly understood. We selected the pleural fluid mononuclear cells (PFMCs) from TBP and PBMCs from healthy donors (HD), and characterized PD‐1‐expresing T‐cell phenotypes and functions. Here, we found that the PFMCs exhibited increases in numbers of PD‐1‐expressing CD4+ and CD8+ T cells, which preferentially displayed polarized effector memory phenotypes. The M.tb‐specific Ag stimulation increased CD4+PD‐1+ and CD8+PD‐1+ T cells, which is in direct correlation with IFN‐γ production and PD‐L1+ APCs in PFMCs of these individuals. Moreover, blockage of PD‐1/PD‐L1 pathway enhanced the percentage of IFN‐γ+ T cells, demonstrating that the PD‐1/PD‐L1 pathway played a negative regulation in T cell effector functions. Furthermore, CD4+PD‐1+ and CD8+PD‐1+ T‐cell subsets showed greater memory phenotype, activation, and effector functions for producing Th1 cytokines than PD‐1− counterparts. Thus, these PD‐1+ T cells were not exhausted but appear to be central to maintaining Ag‐specific effector. IL‐12, a key immunoregulatory cytokine, enhanced the expression of PD‐1 and restored a strong IFN‐γ response through selectively inducing the phosphorylation of STAT4 in CD4+PD‐1+T‐bet+ and CD8+PD‐1+T‐bet+ T cells. This study therefore uncovered a previously unknown mechanism for T‐cell immune responses regulated by PD‐1, and may have implications for potential immune intervention in TBP.

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Core Concepts in Immunology: The Definition of Autoimmunity and Its Unique Application to the Seat of Tolerance, the Liver

Zigmond

Shetty

2020

Liver Immunology

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The chronicles of T-cell exhaustion

Cited by 26 publications

References 12 publications

Atezolizumab for the treatment of non-small cell lung cancer

Atezolizumab for the treatment of non-small cell lung cancer

PD-1 modulating Mycobacterium tuberculosis-specific polarized effector memory T cells response in tuberculosis pleurisy

Core Concepts in Immunology: The Definition of Autoimmunity and Its Unique Application to the Seat of Tolerance, the Liver

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