Blocking TIM-3 reinvigorates exhausted CD8 T cells with no impact on NK cell function in ART-treated HIV-infected patients

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

Download Full-text

Expression and function of NK cell receptors in CD8+ T cells

Current Opinion in Immunology ◽

10.1016/s0952-7915(00)00242-9 ◽

2001 ◽

Vol 13 (4) ◽

pp. 465-470 ◽

Cited By ~ 122

Author(s):

Christopher W McMahon ◽

David H Raulet

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Nk Cell ◽

Cell Receptors ◽

Nk Cell Receptors ◽

And Function

Download Full-text

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

Journal of Virology ◽

10.1128/jvi.01541-18 ◽

2018 ◽

Vol 93 (3) ◽

Cited By ~ 7

Author(s):

Abena K. R. Kwaa ◽

Chloe A. G. Talana ◽

Joel N. Blankson

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Effector Cell ◽

Cell Function ◽

Nk Cell ◽

Suppressive Capacity ◽

Short Course ◽

Shock And Kill ◽

Hiv 1

ABSTRACTCurrent shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-α) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-α treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-α enhanced global CP CD8+T cell cytokine responses and the suppressive capacity of ES CD8+T cells. Our data suggest that IFN-α treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCEData suggest that HIV+individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-α) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+T cell function. These results point to the possibility of exploring such short-course IFN-α treatments for the enhancement of effector cell function in HIV+patients in future cure strategies.

Download Full-text

Low NK cell abundance correlates with high expression of PD-1 in CD8+ T cells

Annals of Oncology ◽

10.1093/annonc/mdz268.034 ◽

2019 ◽

Vol 30 ◽

pp. v772

Author(s):

M.H. Lee ◽

P. Järvinen ◽

H. Nísen ◽

O. Bruck ◽

M. Ilander ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Nk Cell ◽

High Expression ◽

Cell Abundance

Download Full-text

Serum-derived exosomes promote CD8+ T cells to overexpress PD-1, affecting the prognosis of hypopharyngeal carcinoma

Cancer Cell International ◽

10.1186/s12935-021-02294-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qian Gao ◽

Hui-Ting Liu ◽

Yu-Qin Xu ◽

Lin Zhang ◽

Yuan-Ru Liu ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Cd8 T Cells ◽

Poor Prognosis ◽

Cell Function ◽

Immune Escape ◽

Cd8 T Cell ◽

Serum Exosomes

Abstract Background Hypopharyngeal cancer (HPC) is associated with a poor prognosis and a high recurrence rate. Immune escape is one of the reasons for the poor prognosis of malignant tumors. Programmed cell death ligand 1 (PD-L1) and programmed cell death-1 (PD-1) have been shown to play important roles in immune escape. However, the role of PD-1/PD-L1 in HPC remains unclear. In this experiment, we investigated the effect of exosomes from HPC patient serum on CD8+ T cell function and PD-1/PD-L1 expression and, thus, on prognosis. We hope to provide guidance for the identification of new targets for HPC immunotherapy. Methods PD-1 and CD8 expression in 71 HPC tissues and 16 paracarcinoma tissues was detected by immunohistochemistry. Concurrently, the clinicopathological data of the patients were obtained to conduct correlation analysis. Exosomes were isolated from serum and then identified by Western blotting (WB), transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). Flow cytometry was used to assess the activity of CD8+ T cells after exosome stimulation. The effects of exosomes on the ability of CD8+ T cells to kill FaDu cells were assessed by CCK-8 assay. The expression of IL-10 and TGF-β1 was measured by enzyme-linked immunosorbent assay (ELISA). PD-L1 expression in HPC tissue samples was evaluated by immunohistochemistry, and the relationship between PD-1/PD-L1 expression and prognosis was investigated with patient specimens. Results PD-1 expression was significantly upregulated on CD8+ T cells in tumor tissues compared with those in normal tissues. The overall survival (OS) and disease-free survival (DFS) of PD-1-overexpressing patients were decreased. Serum exosomes from patients can elevate PD-1 expression on CD8+ T cells and suppress their killing capacity and secretory function. The rate of positive PD-L1 expression was increased in HPC tissues compared with paracancerous tissues. The DFS and OS of the PD-1(+)-PD-L1(+) group were significantly lower than those of the PD-1(−)-PD-L1(−) group. Conclusion Our findings indicate that serum exosomes from HPC patients can inhibit CD8+ T cell function and that the PD-1-PD-L1 pathway plays an important role in the immune escape of HPC. Exosomes combined with immunotherapy may guide the treatment of patients with advanced disease in the future.

Download Full-text

Divergent Impact of Glucose Availability on Human Virus-Specific and Generically Activated CD8 T Cells

Metabolites ◽

10.3390/metabo10110461 ◽

2020 ◽

Vol 10 (11) ◽

pp. 461

Author(s):

Jenifer Sanchez ◽

Ian Jackson ◽

Katie R. Flaherty ◽

Tamara Muliaditan ◽

Anna Schurich

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Function ◽

Cd8 T Cell ◽

Cell Immune Response ◽

Complex Nature ◽

Human Virus ◽

Glucose Availability

Upon activation T cells engage glucose metabolism to fuel the costly effector functions needed for a robust immune response. Consequently, the availability of glucose can impact on T cell function. The glucose concentrations used in conventional culture media and common metabolic assays are often artificially high, representing hyperglycaemic levels rarely present in vivo. We show here that reducing glucose concentration to physiological levels in culture differentially impacted on virus-specific compared to generically activated human CD8 T cell responses. In virus-specific T cells, limiting glucose availability significantly reduced the frequency of effector-cytokine producing T cells, but promoted the upregulation of CD69 and CD103 associated with an increased capacity for tissue retention. In contrast the functionality of generically activated T cells was largely unaffected and these showed reduced differentiation towards a residency phenotype. Furthermore, T cells being cultured at physiological glucose concentrations were more susceptible to viral infection. This setting resulted in significantly improved lentiviral transduction rates of primary cells. Our data suggest that CD8 T cells are exquisitely adapted to their niche and provide a reminder of the need to better mimic physiological conditions to study the complex nature of the human CD8 T cell immune response.

Download Full-text

Immunosuppressive effects of pentostatin.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.5.848 ◽

1990 ◽

Vol 8 (5) ◽

pp. 848-855 ◽

Cited By ~ 62

Author(s):

E H Kraut ◽

J C Neff ◽

B A Bouroncle ◽

D Gochnour ◽

M R Grever

Keyword(s):

T Cells ◽

B Cells ◽

Cell Function ◽

Nk Cell ◽

Investigational Drug ◽

Cd8 Cells ◽

Immune Parameters ◽

Before And After ◽

Significant Depression ◽

Normal Monocyte

The immune function of patients with hairy cell leukemia (HCL) and solid tumors was evaluated before and after treatment with the investigational drug 2'-deoxycoformycin (pentostatin; dCF). Thirteen HCL patients received doses of dCF of 2 to 4 mg/m2 intravenously at 2- to 6-week intervals for up to 15 courses. After completion of treatment, 12 of 13 patients had resolution of severe monocytopenia and five of nine had normal monocyte antibody dependent cellular cytotoxicity. There was statistically significant depression of total lymphocytes, T cells, and B cells. Evaluation of T subsets showed a decrease in CD4+ cells. Immunoglobulin G (IgG) in sera were decreased from baseline, while IgM and IgA were unaffected. There was no significant effect on skin-test reactivity or large granular lymphocyte numbers. Lymphoblastic transformation was variably affected. Natural-killer (NK) cell function was improved or unchanged after dCF treatment. Reevaluation of seven patients at 21 to 119 weeks after receiving dCF demonstrated that recovery to normal T- and B-cell numbers and subsets does occur. Five solid tumor patients were given dCF at 4 mg/m2 intravenously at 1- to 2-week intervals for up to five courses. There was significant reduction in T cells, B cells, CD4+, and CD8+ cells with no statistically significant effect on the other immune parameters. We conclude that low doses of dCF can cause persistent immunosuppression though recovery may occur after the drug is stopped. In patients followed after completion of dCF, there was no associated increase in second malignancies or unusual infections.

Download Full-text

Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF

Nature Medicine ◽

10.1038/nm.2232 ◽

2010 ◽

Vol 16 (10) ◽

pp. 1147-1151 ◽

Cited By ~ 276

Author(s):

Michael Quigley ◽

Florencia Pereyra ◽

Björn Nilsson ◽

Filippos Porichis ◽

Catia Fonseca ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Function ◽

Transcriptional Analysis ◽

T Cell Function

Download Full-text

Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44

Blood ◽

10.1182/blood-2004-12-4802 ◽

2005 ◽

Vol 106 (6) ◽

pp. 2076-2082 ◽

Cited By ~ 103

Author(s):

Anja Fuchs ◽

Marina Cella ◽

Takayuki Kondo ◽

Marco Colonna

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Nk Cell ◽

Close Contact ◽

Killer Cell ◽

Adaptor Protein ◽

Interferon Α ◽

Memory Cd8 T Cells ◽

Activating Receptor

Abstract Natural killer (NK) cell-mediated cytotoxicity is triggered by multiple activating receptors associated with the signaling adaptor protein DNAX activation protein 12/killer cell-activating receptor-associated protein (DAP12/KARAP). Here, we show that one of these receptors, NKp44, is present on a subset of natural interferon-producing cells (IPCs) in tonsils. NKp44 expression can also be induced on blood IPCs after in vitro culture with interleukin 3 (IL-3). Crosslinking of NKp44 does not trigger IPC-mediated cytotoxicity but, paradoxically, inhibits interferon α (IFN-α) production by IPCs in response to cytosine-phosphate-guanosine (CpG) oligonucleotides. We find that IPCs in tonsils are in close contact with CD8+ T cells and demonstrate that a subset of memory CD8+ T cells produces IL-3. Therefore, IL-3-mediated induction of NKp44 on IPCs may be an important component of the ongoing crosstalk between the innate and adaptive immune response that allows memory CD8+ T cells to control the IPC response to virus. (Blood. 2005;106: 2076-2082)

Download Full-text

Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease

Blood ◽

10.1182/blood.v96.12.3872 ◽

2000 ◽

Vol 96 (12) ◽

pp. 3872-3879 ◽

Cited By ~ 108

Author(s):

Viola Hoffacker ◽

Anja Schultz ◽

James J. Tiesinga ◽

Ralf Gold ◽

Berthold Schalke ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Autoimmune Disease ◽

Cd8 T Cells ◽

Cell Function ◽

Cell Subset ◽

Cell Repertoire ◽

T Cell Subset ◽

Functional Studies ◽

Circulating T Cells

Abstract Thymomas are the only tumors that are proven to generate mature T cells from immature precursors. It is unknown, however, whether intratumorous thymopoiesis has an impact on the peripheral T-cell pool and might thus be related to the high frequency of thymoma-associated myasthenia gravis. This study shows, using fluorescence-activated cell sorting-based analyses and T-cell proliferation assays, that thymopoiesis and T-cell function in thymomas correspond with immunologic alterations in the blood. Specifically, the proportion of circulating CD45RA+CD8+ T cells is significantly increased in patients with thymoma compared with normal controls, in accordance with intratumorous T-cell development that is abnormally skewed toward the CD8+ phenotype. Moreover, it is primarily the proportion of circulating CD45RA+CD8+ T cells that decreases after thymectomy. The results also demonstrate that T cells reactive toward recombinant autoantigens are distributed equally between thymomas and blood, whereas T-cell responses to foreign antigen (ie, tetanus toxoid) are seen only among circulating T cells and not among thymoma-derived T cells. These functional studies support the hypothesis that thymopoiesis occurring within thymomas alters the peripheral T-cell repertoire. Because many thymomas are enriched with autoantigen-specific T cells, a disturbance of circulating T-cell subset composition by export of intratumorous T cells may contribute to paraneoplastic autoimmune disease arising in patients with thymoma.

Download Full-text