Tissue-Specific Abundance of Regulatory T Cells Correlates with CD8+T Cell Dysfunction and Chronic Retrovirus Loads

Key Points PD-L1/PD-1–mediated CD8 T-cell dysfunction develops with CLL in different organs, and similarities to aging-related immune defects exist. PD-1+ normal T cells have markedly different effector functions than PD-1+ CLL T cells.

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Transforming growth factor beta orchestrates PD-L1 enrichment in tumor-derived exosomes and mediates CD8 T-cell dysfunction regulating early phosphorylation of TCR signalome in breast cancer

Carcinogenesis ◽

10.1093/carcin/bgaa092 ◽

2020 ◽

Author(s):

Soumya Chatterjee ◽

Annesha Chatterjee ◽

Samir Jana ◽

Subhasis Dey ◽

Himansu Roy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Evasion ◽

Cd8 T Cells ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Cd8 T Cell ◽

Cell Dysfunction ◽

T Cell Dysfunction ◽

Growth Factor Beta

Abstract Tumor cells promote immune evasion through upregulation of programmed death-ligand 1 (PD-L1) that binds with programmed cell death protein 1 (PD1) on cytotoxic T cells and promote dysfunction. Though therapeutic efficacy of anti-PD1 antibody has remarkable effects on different type of cancers it is less effective in breast cancer (BC). Hence, more details understanding of PD-L1-mediated immune evasion is necessary. Here, we report BC cells secrete extracellular vesicles in form of exosomes carry PD-L1 and are highly immunosuppressive. Transforming growth factor beta (TGF-β) present in tumor microenvironment orchestrates BC cell secreted exosomal PD-L1 load. Circulating exosomal PD-L1 content is highly correlated with tumor TGF-β level. The later also found to be significantly associated with CD8+CD39+, CD8+PD1+ T-cell phenotype. Recombinant TGF-β1 dose dependently induces PD-L1 expression in Texos in vitro and blocking of TGF-β dimmed exosomal PD-L1 level. PD-L1 knocked down exosomes failed to suppress effector activity of activated CD8 T cells like tumor exosomes. While understanding its effect on T-cell receptor signaling, we found siPD-L1 exosomes failed to block phosphorylation of src family proteins, linker for activation of T cells and phosphoinositide phospholipase Cγ of CD8 T cells more than PD-L1 exosomes. In vivo inhibition of exosome release and TGF-β synergistically attenuates tumor burden by promoting Granzyme and interferon gamma release in tumor tissue depicting rejuvenation of exhausted T cells. Thus, we establish TGF-β as a promoter of exosomal PD-L1 and unveil a mechanism that tumor cells follow to promote CD8 T-cell dysfunction.

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Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis

Journal of Experimental Medicine ◽

10.1084/jem.20151995 ◽

2016 ◽

Vol 213 (9) ◽

pp. 1799-1818 ◽

Cited By ~ 35

Author(s):

SuJin Hwang ◽

Dustin A. Cobb ◽

Rajarshi Bhadra ◽

Ben Youngblood ◽

Imtiaz A. Khan

Keyword(s):

T Cells ◽

T Cell ◽

Critical Role ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

T Cell Exhaustion ◽

Cell Exhaustion ◽

Cell Dysfunction ◽

T Cell Dysfunction

CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)–susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell–intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches.

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TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection

Gut ◽

10.1136/gutjnl-2020-322404 ◽

2020 ◽

pp. gutjnl-2020-322404

Author(s):

Kathrin Heim ◽

Benedikt Binder ◽

Sagar ◽

Dominik Wieland ◽

Nina Hensel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Hbv Infection ◽

T Cell Exhaustion ◽

Cell Exhaustion ◽

Cell Dysfunction ◽

Chronic Hepatitis B Virus ◽

T Cell Dysfunction

ObjectiveChronic hepatitis B virus (HBV) infection is characterised by HBV-specific CD8+ T cell dysfunction that has been linked to Tcell exhaustion, a distinct differentiation programme associated with persisting antigen recognition. Recently, Thymocyte Selection-Associated High Mobility Group Box (TOX) was identified as master regulator of CD8+ T cell exhaustion. Here, we addressed the role of TOX in HBV-specific CD8+ T cell dysfunction associated with different clinical phases of infection.DesignWe investigated TOX expression in HBV-specific CD8+ T cells from 53 HLA-A*01:01, HLA-A*11:01 and HLA-A*02:01 positive patients from different HBV infection phases and compared it to hepatitis C virus (HCV)-specific, cytomegalovirus (CMV)-specific, Epstein-Barr virus (EBV)-specific and influenza virus (FLU)-specific CD8+ T cells. Phenotypic and functional analyses of virus-specific CD8+ T cells were performed after peptide-loaded tetramer-enrichment and peptide-specific expansion.ResultsOur results show that TOX expression in HBV-specific CD8+ T cells is linked to chronic antigen stimulation, correlates with viral load and is associated with phenotypic and functional characteristics of T-cell exhaustion. In contrast, similar TOX expression in EBV-specific and CMV-specific CD8+ T cells is not linked to T-cell dysfunction suggesting different underlying programmes. TOX expression in HBV-specific CD8+ T cells is also affected by targeted antigens, for example, core versus polymerase. In HBV-specific CD8+ T cells, TOX expression is maintained after spontaneous or therapy-mediated viral control in chronic but not self-limiting acute HBV infection indicating a permanent molecular imprint after chronic but not temporary stimulation.ConclusionOur data highlight TOX as biomarker specific for dysfunctional virus-specific CD8+ T cells in the context of an actively persisting infection.

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Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells

Journal of Experimental Medicine ◽

10.1084/jem.20142237 ◽

2015 ◽

Vol 212 (7) ◽

pp. 1125-1137 ◽

Cited By ~ 190

Author(s):

Pamela M. Odorizzi ◽

Kristen E. Pauken ◽

Michael A. Paley ◽

Arlene Sharpe ◽

E. John Wherry

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Lymphocytic Choriomeningitis ◽

T Cell Exhaustion ◽

Cell Exhaustion ◽

Cell Dysfunction ◽

T Cell Dysfunction ◽

T Cell Survival

Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8+ T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established “exhausted” CD8+ T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8+ T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8+ TEX cells. These results demonstrate that CD8+ T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.

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The Evolving Role of CD8+CD28− Immunosenescent T Cells in Cancer Immunology

International Journal of Molecular Sciences ◽

10.3390/ijms20112810 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2810 ◽

Cited By ~ 11

Author(s):

Wei X. Huff ◽

Jae Hyun Kwon ◽

Mario Henriquez ◽

Kaleigh Fetcko ◽

Mahua Dey

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Costimulatory Molecule ◽

Tumor Immunotherapy ◽

Cd8 T Cell ◽

Cell Senescence ◽

Cell Dysfunction ◽

T Cell Dysfunction ◽

T Cell Senescence

Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized—tolerance, anergy, exhaustion, and senescence—CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28− senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28− senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy.

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Do Foxp3+ Regulatory T Cells (Treg Cells) Play a Role in the Immunopathogenesis of Primary/Idiopathic Minimal Change Disease?

ISRN Pathology ◽

10.1155/2014/640829 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Susan Swee-Shan Hue ◽

Sufi Muhammad Suhail ◽

Jason Chon Jun Choo ◽

Nurhashikin Yusof ◽

Alwin Hwai-Liang Loh ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

T Cell Activation ◽

Cell Activation ◽

Minimal Change Disease ◽

Minimal Change ◽

Glomerular Permeability ◽

Cell Dysfunction ◽

T Cell Dysfunction

Minimal change disease constitutes a major cause of nephrotic syndrome. It is regarded as a non-immune-complex mediated primary glomerulopathy and pathogenetically is characterised by podocyte injury and effacement of foot processes; therefore, it is also classified as a type of podocytopathy. T cell dysfunction with increased levels of a soluble glomerular permeability factor has been proposed to play a major role in the pathogenesis of minimal change disease. It has been therefore suggested that a dysfunction of regulatory T cells, the orchestrators of immune homeostasis, could be implicated in perpetuating T cell activation in this condition. However, the actual contribution of regulatory T cell dysfunction in the immunopathogenesis of primary minimal change disease is still largely unclear. We here propose a theoretical model based on the available evidence.

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HBV-Specific CD8+ T-Cell Tolerance in the Liver

Frontiers in Immunology ◽

10.3389/fimmu.2021.721975 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ian Baudi ◽

Keigo Kawashima ◽

Masanori Isogawa

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

T Cell ◽

Hepatitis B ◽

Mouse Models ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Cell Dysfunction ◽

Cell Responses ◽

T Cell Dysfunction

Hepatitis B virus (HBV) remains a leading cause of liver-related morbidity and mortality through chronic hepatitis that may progress to liver cirrhosis and cancer. The central role played by HBV-specific CD8+ T cells in the clearance of acute HBV infection, and HBV-related liver injury is now well established. Vigorous, multifunctional CD8+ T cell responses are usually induced in most adult-onset HBV infections, while chronic hepatitis B (CHB) is characterized by quantitatively and qualitatively weak HBV-specific CD8+ T cell responses. The molecular basis of this dichotomy is poorly understood. Genomic analysis of dysfunctional HBV-specific CD8+ T cells in CHB patients and various mouse models suggest that multifaceted mechanisms including negative signaling and metabolic abnormalities cooperatively establish CD8+ T cell dysfunction. Immunoregulatory cell populations in the liver, including liver resident dendritic cells (DCs), hepatic stellate cells (HSCs), myeloid-derived suppressor cells (MDSCs), may contribute to intrahepatic CD8+ T cell dysfunction through the production of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines and the expression of co-inhibitory molecules. A series of recent studies with mouse models of HBV infection suggest that genetic and epigenetic changes in dysfunctional CD8+ T cells are the manifestation of prolonged antigenic stimulation, as well as the absence of co-stimulatory or cytokine signaling. These new findings may provide potential new targets for immunotherapy aiming at invigorating HBV-specific CD8+ T cells, which hopefully cures CHB.

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