The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1 immune responses

Abstract Among prostaglandins (PGs), PGE2 is abundantly expressed in various malignancies and is probably one of many factors promoting tumor growth by inhibiting tumor immune surveillance. In the current study, we report on a novel mechanism by which PGE2 inhibits in vitro natural killer–dendritic cell (NK-DC) crosstalk and thereby innate and adaptive immune responses via its effect on NK-DC crosstalk. The presence of PGE2 during IFN-γ/membrane fraction of Klebsiella pneumoniae DC maturation inhibits the production of chemokines (CCL5, CCL19, and CXCL10) and cytokines (IL-12 and IL-18), which is cAMP-dependent and imprinted during DC maturation. As a consequence, these DCs fail to attract NK cells and show a decreased capacity to trigger NK cell IFN-γ production, which in turn leads to reduced T-helper 1 polarization. In addition, the presence of PGE2 during DC maturation impairs DC-mediated augmentation of NK-cell cytotoxicity. Opposed to their inhibitory effects on peripheral blood–derived NK cells, PGE2 matured DCs induce IL-22 secretion of inflammation constraining NKp44+ NK cells present in mucosa-associated lymphoid tissue. The inhibition of NK-DC interaction is a novel regulatory property of PGE2 that is of possible relevance in dampening immune responses in vivo.

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Abstract P216: Inhibition Of T Cell Activation In Response To Placental Ischemia During Pregnancy Improves Hypertension And Activation Of Natural Killer Cells

Hypertension ◽

10.1161/hyp.76.suppl_1.p216 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Nathan Campbell ◽

Evangeline M Deer ◽

Lorena M Amaral ◽

Kristen Reeve ◽

Sarah Fitzgerald ◽

...

Keyword(s):

Blood Pressure ◽

T Cells ◽

T Cell ◽

Nk Cells ◽

Natural Killer ◽

T Cell Activation ◽

T Helper Cells ◽

Cell Activation ◽

T Helper ◽

Placental Ischemia

Preeclampsia (PE), new onset hypertension during pregnancy, is the leading cause of death and morbidity world-wide for the mother and fetus during pregnancy. The Reduced Uterine Perfusion Pressure Rat Model of PE (RUPP) exhibits many characteristics of PE including hypertension, suppressed regulatory T cells (T RegS ) associated with increased CD4+ T cells and B cells secreting agonistic autoantibodies to the AngII receptor (AT1-AA). We have previously shown that blockade of T-helper cells improves blood pressure and lowers AT1-AA secretion. A potential mechanism for the decreased blood pressure is decreased cytolytic natural killer (cNK) cells. Abatacept (Aba) is a fusion molecule designed to inhibit T cell co-stimulation in response to antigens and is used to treat autoimmune diseases. We hypothesize that treatment with Aba will prevent the activation of T-helper cells and therefore lower AT1-AA as a mechanism leading to less cNK cells in response to placental ischemia in RUPP rats. Aba was given on day 13 via the jugular vein. On day 19, blood and tissues were collected, blood pressure (MAP), pup weight, and NK cells were measured by flow cytometry in the blood and placenta. A one-way ANOVA was used for statistical analysis. On GD19, MAP significantly increased in RUPP 119±2 mmHg (n=7, p<0.05) compared to NP controls 102±2 mmHg (n=7) and was normalized with Aba (100±2 mmHg (n=10, p<0.05). Compared to the NP controls (2.2±0.06, n=7), pup weight significantly decreased in RUPP (2±0.08, n=7, p<0.05) but was 2± 0.07, with Aba (n=10). Circulating and placental total NK cells were 32±5, 44±13, % gate in NP rats (n=7), 59±4, 60±16 % gate in RUPP rats (n=7, p<0.05; n=4), which significantly decreased to 40±6, 28±8 % gate with Aba (n=10, p<0.05; n=11). Our findings indicate that prevention of T cell activation lowers total NK cell number and blood pressure in response to placental ischemia of pregnancy.

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Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

Cells ◽

10.3390/cells10061332 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1332

Author(s):

Suresh Gopi Kalathil ◽

Yasmin Thanavala

Keyword(s):

T Cells ◽

T Cell ◽

Viral Hepatitis ◽

Nk Cells ◽

Natural Killer ◽

Functional Impairment ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Current Status ◽

First Line

Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC.

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Interferon-producing Cells Fail to Induce Proliferation of Naive T Cells but Can Promote Expansion and T Helper 1 Differentiation of Antigen-experienced Unpolarized T Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021091 ◽

2003 ◽

Vol 197 (7) ◽

pp. 899-906 ◽

Cited By ~ 127

Author(s):

Anne Krug ◽

Ravi Veeraswamy ◽

Andrew Pekosz ◽

Osami Kanagawa ◽

Emil R. Unanue ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Mhc Class Ii ◽

Type I ◽

T Helper ◽

T Helper 1 ◽

Naive T Cells ◽

Naïve T Cells ◽

Antigen Presenting

Interferon-producing cells (IPCs) secrete high levels of type I interferon in response to certain viruses. The lack of lineage markers, the expression of major histocompatibility complex (MHC) class II and the capacity to stimulate allogeneic T cells have led these cells to be classified as a subset of dendritic cells (DCs), called plasmacytoid DCs (PDCs). However, the role of IPCs/PDCs in initiating primary immune responses remains elusive. Here we examined the antigen presenting capacity of murine IPCs in antigen specific systems. While CD8α+ and CD11b+ DCs induced logarithmic expansion of naive CD4 and CD8 T cells, without conferring T helper commitment at a first encounter, primary IPCs lacked the ability to stimulate naive T cells. However, when antigen-experienced, nonpolarized T cells expanded by classical DC subsets, were restimulated by IPCs, they proliferated and produced high amounts of IFN-γ. These data indicate that IPCs can effectively stimulate preactivated or memory-type T cells and exert an immune-regulatory role. They also suggest that expansion of naive T cells and acquisition of effector function during antigen-specific T cell responses may involve different antigen-presenting cell (APC) types. Independent and coordinated control of T cell proliferation and differentiation would provide the immune system with greater flexibility in regulating immune responses.

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Attenuation of antigen-specific T helper 1 immunity by Neolitsea hiiranensis and its derived terpenoids

PeerJ ◽

10.7717/peerj.2758 ◽

2016 ◽

Vol 4 ◽

pp. e2758 ◽

Cited By ~ 3

Author(s):

Yin-Hua Cheng ◽

Ih-Sheng Chen ◽

Ying-Chi Lin ◽

Chun-Wei Tung ◽

Hsun-Shuo Chang ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Caryophyllene Oxide ◽

Immune Disorders ◽

T Helper ◽

T Helper 1 ◽

Adaptive Immune Responses ◽

Adaptive Immune

Background T cells play a pivotal role in the adaptive immunity that participates in a wide range of immune responses through a complicated cytokine network. Imbalance of T-cell responses is involved in several immune disorders. Neolitsea species, one of the biggest genera in the family Lauraceae, have been employed widely as folk medicines for a long time in Asia. Previous phytochemical investigations revealed the abundance of terpenes in the leaves of N. hiiranensis, an endemic Neolitsea in Taiwan, and demonstrated anti-inflammatory activities. However, the effect of N. hiiranensis on the functionality of immune cells, especially T cells, is still unclear. In this study, we utilize in vitro and in vivo approaches to characterize the effects of leaves of N. hiiranensis and its terpenoids on adaptive immune responses. Methods Dried leaves of N. hiiranensis were extracted three times with cold methanol to prepare crude extracts and to isolate its secondary metabolites. The ovalbumin (OVA)-sensitized BALB/c mice were administrated with N. hiiranensis extracts (5–20 mg/kg). The serum and splenocytes of treated mice were collected to evaluate the immunomodulatory effects of N. hiiranensis on the production of OVA-specific antibodies and cytokines. To further identify the N. hiiranensis-derived compounds with immunomodulatory potentials, OVA-primed splenocytes were treated with compounds isolated from N. hiiranensis by determining the cell viability, cytokine productions, and mRNA expression in the presence of OVA in vitro. Results Crude extracts of leaves of N. hiiranensis significantly inhibited IL-12, IFN-γ, and IL-2 cytokine productions as well as the serum levels of antigen-specific IgM and IgG2a in vivo. Two of fourteen selected terpenoids and one diterpenoid derived from the leaves of N. hiiranensis suppressed IFN-γ in vitro. In addition, β-caryophyllene oxide attenuated the expression of IFN-γ, T-bet, and IL-12Rβ2 in a dose-dependent manner. N. hiiranensis-derived β-caryophyllene oxide inhibited several aspects of adaptive immune responses, including T-cell differentiation, IFN-γ production, and Th1-assocaited genes. Conclusion As IFN-γ is the key cytokine secreted by T helper-1 cells and plays a pivotal role in Th1 immune responses, our results suggested that the N. hiiranensis and its terpenoids may possess potential therapeutic effects on Th1-mediated immune disorders.

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Faculty Opinions recommendation of Natural killer (NK)-dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4+ T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13364975.14735081 ◽

2011 ◽

Author(s):

Jacques Zimmer

Keyword(s):

T Cells ◽

Dendritic Cell ◽

Nk Cells ◽

Natural Killer ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Class Ii ◽

Cell Interactions

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OX40L–OX40 Signaling in Atopic Dermatitis

Journal of Clinical Medicine ◽

10.3390/jcm10122578 ◽

2021 ◽

Vol 10 (12) ◽

pp. 2578

Author(s):

Masutaka Furue ◽

Mihoko Furue

Keyword(s):

T Cells ◽

Atopic Dermatitis ◽

Memory T Cells ◽

Effector Memory ◽

T Helper ◽

T Helper 1 ◽

Therapeutic Success ◽

T Helper 2 ◽

Promising Target ◽

Antigen Presenting

OX40 is one of the co-stimulatory molecules expressed on T cells, and it is engaged by OX40L, primarily expressed on professional antigen-presenting cells such as dendritic cells. The OX40L–OX40 axis is involved in the sustained activation and expansion of effector T and effector memory T cells, but it is not active in naïve and resting memory T cells. Ligation of OX40 by OX40L accelerates both T helper 1 (Th1) and T helper 2 (Th2) effector cell differentiation. Recent therapeutic success in clinical trials highlights the importance of the OX40L–OX40 axis as a promising target for the treatment of atopic dermatitis.

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Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy

Cancers ◽

10.3390/cancers13092184 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2184

Author(s):

Valentina Cazzetta ◽

Sara Franzese ◽

Claudia Carenza ◽

Silvia Della Bella ◽

Joanna Mikulak ◽

...

Keyword(s):

Liver Cancer ◽

Immune Responses ◽

Nk Cells ◽

Natural Killer ◽

Tumor Cells ◽

Primary Liver Cancer ◽

Circulating Antigens ◽

Direct Cytotoxicity ◽

Immune Changes

Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients.

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