Antigen-Specific Inhibition of Effector T Cell Function in Humans after Injection of Immature Dendritic Cells

Immunostimulatory properties of dendritic cells (DCs) are linked to their maturation state. Injection of mature DCs rapidly enhances antigen-specific CD4+ and CD8+ T cell immunity in humans. Here we describe the immune response to a single injection of immature DCs pulsed with influenza matrix peptide (MP) and keyhole limpet hemocyanin (KLH) in two healthy subjects. In contrast to prior findings using mature DCs, injection of immature DCs in both subjects led to the specific inhibition of MP-specific CD8+ T cell effector function in freshly isolated T cells and the appearance of MP-specific interleukin 10–producing cells. When pre- and postimmunization T cells were boosted in culture, there were greater numbers of MP-specific major histocompatibility complex tetramer-binding cells after immunization, but these had reduced interferon γ production and lacked killer activity. These data demonstrate the feasibility of antigen-specific inhibition of effector T cell function in vivo in humans and urge caution with the use of immature DCs when trying to enhance tumor or microbial immunity.

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DC-Based Vaccines for Cancer Immunotherapy

Vaccines ◽

10.3390/vaccines8040706 ◽

2020 ◽

Vol 8 (4) ◽

pp. 706

Author(s):

Chunmei Fu ◽

Li Zhou ◽

Qing-Sheng Mi ◽

Aimin Jiang

Keyword(s):

Clinical Trials ◽

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd8 T Cells ◽

Critical Role ◽

Cd8 T Cell ◽

T Cell Immunity ◽

Cell Responses ◽

Cell Immunity

As the sentinels of the immune system, dendritic cells (DCs) play a critical role in initiating and regulating antigen-specific immune responses. Cross-priming, a process that DCs activate CD8 T cells by cross-presenting exogenous antigens onto their MHCI (Major Histocompatibility Complex class I), plays a critical role in mediating CD8 T cell immunity as well as tolerance. Current DC vaccines have remained largely unsuccessful despite their ability to potentiate both effector and memory CD8 T cell responses. There are two major hurdles for the success of DC-based vaccines: tumor-mediated immunosuppression and the functional limitation of the commonly used monocyte-derived dendritic cells (MoDCs). Due to their resistance to tumor-mediated suppression as inert vesicles, DC-derived exosomes (DCexos) have garnered much interest as cell-free therapeutic agents. However, current DCexo clinical trials have shown limited clinical benefits and failed to generate antigen-specific T cell responses. Another exciting development is the use of naturally circulating DCs instead of in vitro cultured DCs, as clinical trials with both human blood cDC2s (type 2 conventional DCs) and plasmacytoid DCs (pDCs) have shown promising results. pDC vaccines were particularly encouraging, especially in light of promising data from a recent clinical trial using a human pDC cell line, despite pDCs being considered tolerogenic and playing a suppressive role in tumors. However, how pDCs generate anti-tumor CD8 T cell immunity remains poorly understood, thus hindering their clinical advance. Using a pDC-targeted vaccine model, we have recently reported that while pDC-targeted vaccines led to strong cross-priming and durable CD8 T cell immunity, cross-presenting pDCs required cDCs to achieve cross-priming in vivo by transferring antigens to cDCs. Antigen transfer from pDCs to bystander cDCs was mediated by pDC-derived exosomes (pDCexos), which similarly required cDCs for cross-priming of antigen-specific CD8 T cells. pDCexos thus represent a new addition in our arsenal of DC-based cancer vaccines that would potentially combine the advantage of pDCs and DCexos.

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FoxP3+Regulatory T Cells Suppress Effector T-Cell Function at Pathologic Site in Miliary Tuberculosis

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.200804-529oc ◽

2009 ◽

Vol 179 (11) ◽

pp. 1061-1070 ◽

Cited By ~ 92

Author(s):

Prabhat K. Sharma ◽

Pradip K. Saha ◽

Amar Singh ◽

Surendra K. Sharma ◽

Balaram Ghosh ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cell Function ◽

Miliary Tuberculosis ◽

Effector T Cell ◽

T Cell Function

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The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function

Journal of Virology ◽

10.1128/jvi.02415-06 ◽

2007 ◽

Vol 81 (6) ◽

pp. 2940-2949 ◽

Cited By ~ 58

Author(s):

Adam J. Gehring ◽

Dianxing Sun ◽

Patrick T. F. Kennedy ◽

Esther Nolte-'t Hoen ◽

Seng Gee Lim ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Viral Antigen ◽

Cell Function ◽

Cd8 T Cell ◽

T Cell Function ◽

Tnf Α ◽

Antiviral Function ◽

Ifn Γ

ABSTRACT CD8 T cells exert their antiviral function through cytokines and lysis of infected cells. Because hepatocytes are susceptible to noncytolytic mechanisms of viral clearance, CD8 T-cell antiviral efficiency against hepatotropic viruses has been linked to their capacity to produce gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). On the other hand, intrahepatic cytokine production triggers the recruitment of mononuclear cells, which sustain acute and chronic liver damage. Using virus-specific CD8 T cells and human hepatocytes, we analyzed the modulation of virus-specific CD8 T-cell function after recognition peptide-pulsed or virally infected hepatocytes. We observed that hepatocyte antigen presentation was generally inefficient, and the quantity of viral antigen strongly influenced CD8 T-cell antiviral function. High levels of hepatitis B virus production induced robust IFN-γ and TNF-α production in virus-specific CD8 T cells, while limiting amounts of viral antigen, both in hepatocyte-like cells and naturally infected human hepatocytes, preferentially stimulated CD8 T-cell degranulation. Our data document a mechanism where virus-specific CD8 T-cell function is influenced by the quantity of virus produced within hepatocytes.

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Histone Deacetylase 11 (HDAC11) Regulates Cytotoxic T-Cell Function and Memory Phenotype

Blood ◽

10.1182/blood.v120.21.840.840 ◽

2012 ◽

Vol 120 (21) ◽

pp. 840-840

Author(s):

David M Woods ◽

Karrune V. Woan ◽

Eva Sahakian ◽

John Powers ◽

Fengdong Cheng ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Function ◽

Cd8 T Cell ◽

Central Memory ◽

Negative Regulator ◽

Wild Type ◽

Potential Target ◽

T Cell Function

Abstract Abstract 840 T-cells are an essential component of immune mediated tumor rejection. Adoptive transfer of T-cells results in a durable anti-tumor response in some patients with hematological malignancies. To further improve the efficacy of T-cell adoptive transfers, a better understanding of the regulatory checkpoints of these cells is needed. Here we show that HDAC11 is a negative regulator of CD8+ T-cell function, thus representing a potential target in adoptive immunotherapy. HDACs are a group of enzymes initially known for their role in deacetylating histones, thereby condensing chromatin structure and repressing gene expression. The known roles of HDACs as epigenetic regulators have recently expanded to include more complex regulatory functions including interactions with non-histone targets. HDAC11 is the most recently identified member of the HDAC family, and is highly expressed in brain, testis and T-cells. Recently, our group reported HDAC11 as a regulator of IL-10 production in antigen presenting cells. To determine the role of HDAC11 in T-cell biology, T-cells from HDAC11 knock out (HDAC11KO) mice were compared to wild-type T-cells in number, function and phenotype. HDAC11KO T-cells had no differences in absolute number or percentages of CD4+ or CD8+ lymphocytes. However CD8+ T-cells were hyper-proliferative upon CD3/CD28 stimulation and produced significantly higher levels of the pro-inflammatory, Tc1 cytokines IL-2, INF-γ, and TNF-α. However, no significant increases in the production of the Tc2 cytokines IL-4, IL-6 or IL-10 were seen. Further investigation of phenotypic differences also revealed that HDAC11KO mice have a larger percentage of central memory CD8+ T-cells. Additionally, HDAC11KO CD8+ T-cells express higher levels of the transcription factor Eomes, a known contributor to central memory cell formation as well as a controller of granzyme B and perforin production in CD8+ T-cells. This Tc1 and central memory-like phenotype translated to delayed tumor progression and survival in vivo in C1498 AML bearing mice treated with adoptively transferred HDAC11KO T-cells, as compared with wild type T-cells. Collectively, we have demonstrated HDAC11 as a negative regulator of CD8+ T-cell function, and a novel potential target to augment the efficacy of adoptive T-cell tumor immunotherapy. Disclosures: No relevant conflicts of interest to declare.

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Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

10.1101/2021.09.23.461402 ◽

2021 ◽

Author(s):

Khalid W Kalim ◽

Jun-Qi Yang ◽

Mark Wunderlich ◽

Vishnu Modur ◽

Phuong Nguyen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Treg Cell ◽

Cell Function ◽

Treg Cells ◽

T Cell Response ◽

T Cell Immunity ◽

Cell Plasticity ◽

Effector T Cell ◽

Cell Immunity

Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T cell function. In the tumor microenvironment, Treg cells are utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes anti-tumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.

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Combination rhIL-15 and Anti-PD-L1 (Avelumab) Enhances HIVGag-Specific CD8 T-Cell Function

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa269 ◽

2020 ◽

Vol 222 (9) ◽

pp. 1540-1549

Author(s):

Bruktawit A Goshu ◽

Hui Chen ◽

Maha Moussa ◽

Jie Cheng ◽

Marta Catalfamo

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Function ◽

Cd8 T Cell ◽

Peripheral Tissues ◽

T Cell Function ◽

Interleukin 15 ◽

Checkpoint Receptors

Abstract In chronic HIV infection, virus-specific cytotoxic CD8 T cells showed expression of checkpoint receptors and impaired function. Therefore, restoration of CD8 T-cell function is critical in cure strategies. Here, we show that in vitro blockade of programmed cell death ligand 1 (PD-L1) by an anti-PD-L1 antibody (avelumab) in combination with recombinant human interleukin-15 (rhIL-15) synergistically enhanced cytokine secretion by proliferating HIVGag-specific CD8 T cells. In addition, these CD8 T cells have a CXCR3+PD1−/low phenotype, suggesting a potential to traffic into peripheral tissues. In vitro, proliferating CD8 T cells express PD-L1 suggesting that anti-PD-L1 treatment also targets virus-specific CD8 T cells. Together, these data indicate that rhIL-15/avelumab combination therapy could be a useful strategy to enhance CD8 T-cell function in cure strategies.

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Protective Immunity against Secondary Poxvirus Infection Is Dependent on Antibody but Not on CD4 or CD8 T-Cell Function

Journal of Virology ◽

10.1128/jvi.00115-06 ◽

2006 ◽

Vol 80 (13) ◽

pp. 6333-6338 ◽

Cited By ~ 79

Author(s):

Vijay Panchanathan ◽

Geeta Chaudhri ◽

Gunasegaran Karupiah

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Primary Infection ◽

Protective Immunity ◽

Cell Function ◽

Secondary Infection ◽

Cd8 T Cell ◽

Ectromelia Virus ◽

T Cell Function

ABSTRACT Renewed interest in smallpox and the need for safer vaccines have highlighted our lack of understanding of the requirements for protective immunity. Since smallpox has been eradicated, surrogate animal models of closely related orthopoxviruses, such as ectromelia virus, have been used to establish critical roles for CD8 T cells in the control of primary infection. To study the requirements for protection against secondary infection, we have used a prime-challenge regime, in which avirulent ectromelia virus was used to prime mice that were then challenged with virulent ectromelia virus. In contrast to primary infection, T cells are not required for recovery from secondary infection, since gene knockout mice deficient in CD8 T-cell function and wild-type mice acutely depleted of CD4, CD8, or both subsets were fully protected. Protection correlated with effective virus control and generation of neutralizing antibody. Notably, primed mice that lacked B cells, major histocompatibility complex class II, or CD40 succumbed to secondary infection. Thus, antibody is essential, but CD4 or CD8 T cells are not required for recovery from secondary poxvirus infection.

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