Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming

T cell exhaustion has been associated with poor prognosis in persistent viral infection and cancer. Conversely, in the context of autoimmunity, T cell exhaustion has been favorably correlated with long-term clinical outcome. Understanding the development of exhaustion in autoimmune settings may provide underlying principles that can be exploited to quell autoreactive T cells. Here, we demonstrate that the adaptor molecule Bat3 acts as a molecular checkpoint of T cell exhaustion, with deficiency of Bat3 promoting a profound exhaustion phenotype, suppressing autoreactive T cell–mediated neuroinflammation. Mechanistically, Bat3 acts as a critical mTORC2 inhibitor to suppress Akt function. As a result, Bat3 deficiency leads to increased Akt activity and FoxO1 phosphorylation, indirectly promoting Prdm1 expression. Transcriptional analysis of Bat3−/− T cells revealed up-regulation of dysfunction-associated genes, concomitant with down-regulation of genes associated with T cell effector function, suggesting that absence of Bat3 can trigger T cell dysfunction even under highly proinflammatory autoimmune conditions.

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52350 PKM2 mediates anti-tumor immunity and T cell dysfunction

Journal of Clinical and Translational Science ◽

10.1017/cts.2021.630 ◽

2021 ◽

pp. 1-2

Author(s):

Geoffrey Markowitz ◽

Yi Ban ◽

Michael Crowley ◽

Diamile Tavarez ◽

Stephen T.C. Wong ◽

...

Keyword(s):

T Cell ◽

Tumor Immunity ◽

Cell Dysfunction ◽

T Cell Dysfunction

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Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy

Nature Communications ◽

10.1038/s41467-021-22407-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jing Liu ◽

Zhihao Zhao ◽

Nasha Qiu ◽

Quan Zhou ◽

Guowei Wang ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Memory Function ◽

Histone Demethylase ◽

Cell Dysfunction ◽

T Cell Infiltration ◽

Programmed Cell Death 1 ◽

T Cell Dysfunction

AbstractAnti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells’ P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.

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Sweet T Cell Dysfunction

American Journal of Transplantation ◽

10.1111/ajt.14729 ◽

2018 ◽

Vol 18 (4) ◽

pp. 775-775

Author(s):

Maria-Luisa Alegre

Keyword(s):

T Cell ◽

Cell Dysfunction ◽

T Cell Dysfunction

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Expansion of Monocytic Myeloid-Derived Suppressor Cells Dampens T Cell Function in HIV-1-Seropositive Individuals

Journal of Virology ◽

10.1128/jvi.01759-12 ◽

2012 ◽

Vol 87 (3) ◽

pp. 1477-1490 ◽

Cited By ~ 111

Author(s):

Aiping Qin ◽

Weiping Cai ◽

Ting Pan ◽

Kang Wu ◽

Qiong Yang ◽

...

Keyword(s):

T Cell ◽

Cell Function ◽

Suppressor Cells ◽

Cell Contact ◽

Myeloid Derived Suppressor Cells ◽

Cell Dysfunction ◽

Arginase 1 ◽

T Cell Function ◽

T Cell Dysfunction ◽

Hiv 1

ABSTRACTT lymphocyte dysfunction contributes to human immunodeficiency virus type 1 (HIV-1) disease progression by impairing antivirus cellular immunity. However, the mechanisms of HIV-1 infection-mediated T cell dysfunction are not completely understood. Here, we provide evidence that expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) suppressed T cell function in HIV-1-infected individuals. We observed a dramatic elevation of M-MDSCs (HLA-DR−/lowCD11b+CD33+/highCD14+CD15−cells) in the peripheral blood of HIV-1-seropositive subjects (n= 61) compared with healthy controls (n= 51), despite efficacious antiretroviral therapy for nearly 2 years. The elevated M-MDSC frequency in HIV-1+subjects correlated with prognostic HIV-1 disease markers, including the HIV-1 load (r= 0.5957;P< 0.0001), CD4+T cell loss (r= −0.5312;P< 0.0001), and activated T cells (r= 0.4421;P= 0.0004). Functional studies showed that M-MDSCs from HIV-1+subjects suppressed T cell responses in both HIV-1-specific and antigen-nonspecific manners; this effect was dependent on the induction of arginase 1 and required direct cell-cell contact. Further investigations revealed that direct HIV-1 infection or culture with HIV-1-derived Tat protein significantly enhanced human MDSC generationin vitro, and MDSCs from healthy donors could be directly infected by HIV-1 to facilitate HIV-1 replication and transmission, indicating that a positive-feedback loop between HIV-1 infection and MDSC expansion existed. In summary, our studies revealed a novel mechanism of T cell dysfunction in HIV-1-infected individuals and suggested that targeting MDSCs may be a promising strategy for HIV-1 immunotherapy.

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Severe Varicella Caused by Varicella-Vaccine Strain in a Child With Significant T-Cell Dysfunction

PEDIATRICS ◽

10.1542/peds.2004-1681 ◽

2007 ◽

Vol 120 (5) ◽

pp. e1345-e1349 ◽

Cited By ~ 28

Author(s):

P. Jean-Philippe ◽

A. Freedman ◽

M. W. Chang ◽

S. P. Steinberg ◽

A. A. Gershon ◽

...

Keyword(s):

T Cell ◽

Vaccine Strain ◽

Varicella Vaccine ◽

Cell Dysfunction ◽

T Cell Dysfunction

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TIGIT Induces (CD3+) T Cell Dysfunction by Inhibiting Glucose Metabolism and its Reversal by TIGIT and/or PD-1 Blockade in Colorectal Cancer

10.21203/rs.3.rs-641407/v1 ◽

2021 ◽

Author(s):

qi shao ◽

Lei Wang ◽

maoling yuan ◽

Xiaohong Jin ◽

changping wu

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

T Cell ◽

Glucose Metabolism ◽

Tumor Growth ◽

Tumor Cells ◽

Peripheral Blood ◽

Cancer Tissue ◽

Cell Dysfunction ◽

T Cell Dysfunction

Abstract Background: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenesis of various tumors, but its immune escape in colorectal cancer remains unclear.Methods: In this study, TIGIT expression in the peripheral blood and tissue microarrays was detected flow cytometry and immunofluorescence and its relationship with prognosis was evaluated. The proliferation and cytokines of TIGIT+ T cells were measured. Glucose metabolism and key enzymes were detected by qPCR or western blot. After establishing the co-cultured system and xenotransplant models, TIGIT antibody alone or combined with PD-1 antibody was blocked to observe the tumor growth.Results: We found that the proportion of CD3+TIGIT+ T cells was increased in peripheral blood and cancer tissue in colorectal cancer patients when compared with the healthy donors. These cells exhibited functional defects, low proliferative activity, impaired cytokine production and reduced glucose metabolism. A strong association was also observed between the elevated TIGIT expression and poor prognosis. In the in vitro co-culture assays of T cells and tumor cells, the suppressed glucose metabolic activity of T cells was reversed by TIGIT blockade. In addition, this blockade induced the apoptosis and reduced G2/M transit in tumor cells. The antitumor efficacy of TIGIT Ab therapy was further demonstrated in a human colorectal xenograft mice model while co-blockers of TIGIT and PD-1 exhibited synergistic suppressing effects on tumor growth.Conclusions: It is suggest that while TIGIT induces CD3+ T cell dysfunction in colorectal cancer, co-targeting TIGIT and PD-1 can lead to an effective antitumor response and may serve as a novel therapeutic strategy for colorectal patients.

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