Inhibition of the DNA damage response phosphatase PPM1D reprograms neutrophils to enhance anti-tumor immune responses

AbstractPPM1D/Wip1 is a negative regulator of the tumor suppressor p53 and is overexpressed in several human solid tumors. Recent reports associate gain-of-function mutations of PPM1D in immune cells with worse outcomes for several human cancers. Here we show that mice with genetic knockout of Ppm1d or with conditional knockout of Ppm1d in the hematopoietic system, in myeloid cells, or in neutrophils all display significantly reduced growth of syngeneic melanoma or lung carcinoma tumors. Ppm1d knockout neutrophils infiltrate tumors extensively. Chemical inhibition of Wip1 in human or mouse neutrophils increases anti-tumor phenotypes, p53-dependent expression of co-stimulatory ligands, and proliferation of co-cultured cytotoxic T cells. These results suggest that inhibition of Wip1 in neutrophils enhances immune anti-tumor responses.

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The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

Journal of Neuroinflammation ◽

10.1186/s12974-020-02057-z ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Tian-Yu Lei ◽

Ying-Ze Ye ◽

Xi-Qun Zhu ◽

Daniel Smerin ◽

Li-Juan Gu ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Immune System ◽

Immune Responses ◽

Ischaemic Stroke ◽

Immune Cells ◽

Tissue Injury ◽

Recovery Period ◽

Vital Functions ◽

Anti Inflammatory

AbstractThrough considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

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Human fetal liver MSCs are more effective than adult bone marrow MSCs for their immunosuppressive, immunomodulatory, and Foxp3+ T reg induction capacity

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02176-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yi Yu ◽

Alejandra Vargas Valderrama ◽

Zhongchao Han ◽

Georges Uzan ◽

Sina Naserian ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Immune Responses ◽

Molecular Mechanisms ◽

Fetal Liver ◽

Cytotoxic T Cells ◽

Cell Contact ◽

Adult Bone Marrow ◽

Adult Bone

Abstract Background Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. Methods MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25−T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. Conclusions These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

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Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

Nature Communications ◽

10.1038/s41467-021-23173-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Alexandra J. Spencer ◽

Paul F. McKay ◽

Sandra Belij-Rammerstorfer ◽

Marta Ulaszewska ◽

Cameron D. Bissett ◽

...

Keyword(s):

Immune Response ◽

Clinical Trials ◽

T Cells ◽

Immune Responses ◽

Viral Vectors ◽

Cytotoxic T Cells ◽

Antibody Responses ◽

Limited Data ◽

Vectored Vaccine ◽

Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

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The Implications of Pruritogens in the Pathogenesis of Atopic Dermatitis

International Journal of Molecular Sciences ◽

10.3390/ijms22137227 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7227

Author(s):

Lai-San Wong ◽

Yu-Ta Yen ◽

Chih-Hung Lee

Keyword(s):

Atopic Dermatitis ◽

Environmental Factors ◽

Immune Responses ◽

Immune Cells ◽

Inflammatory Disease ◽

Targeted Therapies ◽

Skin Barrier ◽

Skin Barrier Function ◽

Inflammatory Molecules

Atopic dermatitis (AD) is a prototypic inflammatory disease that presents with intense itching. The pathophysiology of AD is multifactorial, involving environmental factors, genetic susceptibility, skin barrier function, and immune responses. A recent understanding of pruritus transmission provides more information about the role of pruritogens in the pathogenesis of AD. There is evidence that pruritogens are not only responsible for eliciting pruritus, but also interact with immune cells and act as inflammatory mediators, which exacerbate the severity of AD. In this review, we discuss the interaction between pruritogens and inflammatory molecules and summarize the targeted therapies for AD.

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TAM Receptor Inhibition–Implications for Cancer and the Immune System

Cancers ◽

10.3390/cancers13061195 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1195

Author(s):

Pia Aehnlich ◽

Richard Morgan Powell ◽

Marlies J. W. Peeters ◽

Anne Rahbech ◽

Per thor Straten

Keyword(s):

T Cells ◽

Immune Responses ◽

Cancer Cells ◽

Immune Cells ◽

Tyrosine Kinases ◽

Apoptotic Cell ◽

Receptor Activation ◽

Mouse Tumor ◽

Oncogenic Signaling ◽

Tam Receptors

Tyro3, Axl and MerTK (TAM) receptors are receptor tyrosine kinases which play important roles in efferocytosis and in the balancing of immune responses and inflammation. TAM receptor activation is induced upon binding of the ligands protein S (Pros1) or growth arrest-specific protein 6 (Gas6) which act as bridging molecules for binding of phosphatidyl serine (PtdSer) exposed on apoptotic cell membranes. Upon clearance of apoptotic cell material, TAM receptor activation on innate cells suppresses proinflammatory functions, thereby ensuring the immunologically silent removal of apoptotic material in the absence of deleterious immune responses. However, in T cells, MerTK signaling is costimulatory and promotes activation and functional output of the cell. MerTK and Axl are also aberrantly expressed in a range of both hematological and solid tumor malignancies, including breast, lung, melanoma and acute myeloid leukemia, where they have a role in oncogenic signaling. Consequently, TAM receptors are being investigated as therapeutic targets using small molecule inhibitors and have already demonstrated efficacy in mouse tumor models. Thus, inhibition of TAM signaling in cancer cells could have therapeutic value but given the opposing roles of TAM signaling in innate cells and T cells, TAM inhibition could also jeopardize anticancer immune responses. This conflict is discussed in this review, describing the effects of TAM inhibition on cancer cells as well as immune cells, while also examining the intricate interplay of cancer and immune cells in the tumor microenvironment.

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Direct and Indirect endocrine-mediated suppression of human endometrial CD8+T cell cytotoxicity

Scientific Reports ◽

10.1038/s41598-021-81380-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Z. Shen ◽

M. Rodriguez-Garcia ◽

M. V. Patel ◽

C. R. Wira

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Cytotoxic Activity ◽

Cd8 T Cells ◽

Immune Cells ◽

Cd8 T Cell ◽

Gynecological Cancers ◽

Protective Strategies ◽

T Cell Cytotoxicity

AbstractRegulation of endometrial (EM) CD8+T cells is essential for successful reproduction and protection against pathogens. Suppression of CD8+T cells is necessary for a tolerogenic environment that promotes implantation and pregnancy. However, the mechanisms regulating this process remain unclear. Sex hormones are known to control immune responses directly on immune cells and indirectly through the tissue environment. When the actions of estradiol (E2), progesterone (P) and TGFβ on EM CD8+T cells were evaluated, cytotoxic activity, perforin and granzymes were directly suppressed by E2 and TGFβ but not P. Moreover, incubation of polarized EM epithelial cells with P, but not E2, increased TGFβ secretion. These findings suggest that E2 acts directly on CD8+T cell to suppress cytotoxic activity while P acts indirectly through induction of TGFβ production. Understanding the mechanisms involved in regulating endometrial CD8+T cells is essential for optimizing reproductive success and developing protective strategies against genital infections and gynecological cancers.

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Aedes aegypti (Diptera: Culicidae) Immune Responses with Different Feeding Regimes Following Infection by the Entomopathogenic Fungus Metarhizium anisopliae

Insects ◽

10.3390/insects11020095 ◽

2020 ◽

Vol 11 (2) ◽

pp. 95 ◽

Cited By ~ 1

Author(s):

Sara Cabral ◽

Adriano de Paula ◽

Richard Samuels ◽

Rodrigo da Fonseca ◽

Simone Gomes ◽

...

Keyword(s):

Aedes Aegypti ◽

Immune Responses ◽

Antimicrobial Peptides ◽

Fungal Infection ◽

Fat Body ◽

Negative Regulator ◽

Toll Pathway ◽

Promising Alternative ◽

Imd Pathway ◽

Feeding Regimes

The mosquito Aedes aegypti is the most notorious vector of illness-causing viruses. The use of entomopathogenic fungi as bioinsecticides is a promising alternative for the development of novel mosquito control strategies. We investigate whether differences in immune responses could be responsible for modifications in survival rates of insects following different feeding regimes. Sucrose and blood-fed adult A. aegypti females were sprayed with M. anisopliae 1 × 106 conidia mL−1, and after 48 h, the midgut and fat body were dissected. We used RT-qPCR to monitor the expression of Cactus and REL1 (Toll pathway), IMD, REL2, and Caspar (IMD pathway), STAT and PIAS (JAK-STAT pathway), as well as the expression of antimicrobial peptides (Defensin A, Attacin and Cecropin G). REL1 and REL2 expression in both the midgut and fat body were higher in blood-fed fungus-challenged A. aegypti than in sucrose-fed counterparts. Interestingly, infection of sucrose-fed insects induced Cactus expression in the fat body, a negative regulator of the Toll pathway. The IMD gene was upregulated in the fat body in response to fungal infection after a blood meal. Additionally, we observed the induction of antimicrobial peptides in the blood-fed fungus-challenged insects. This study suggests that blood-fed A. aegypti are less susceptible to fungal infection due to the rapid induction of Toll and IMD immune pathways.

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Inflammasomes inMycobacterium tuberculosis-Driven Immunity

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2017/2309478 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Sebastian Wawrocki ◽

Magdalena Druszczynska

Keyword(s):

Mycobacterium Tuberculosis ◽

Inflammatory Response ◽

Immune Responses ◽

Proinflammatory Cytokines ◽

Immune Cells ◽

Protein Complexes ◽

Inflammasome Activation ◽

Host Immune Responses ◽

Multimeric Protein

The development of effective innate and subsequent adaptive host immune responses is highly dependent on the production of proinflammatory cytokines that increase the activity of immune cells. The key role in this process is played by inflammasomes, multimeric protein complexes serving as a platform for caspase-1, an enzyme responsible for proteolytic cleavage of IL-1βand IL-18 precursors. Inflammasome activation, which triggers the multifaceted activity of these two proinflammatory cytokines, is a prerequisite for developing an efficient inflammatory response against pathogenicMycobacterium tuberculosis(M.tb). This review focuses on the role of NLRP3 and AIM2 inflammasomes inM.tb-driven immunity.

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Traditional Acupuncture Increases the Content of Beta-Endorphin in Immune Cells and Influences Mitogen Induced Proliferation

The American Journal of Chinese Medicine ◽

10.1142/s0192415x91000168 ◽

1991 ◽

Vol 19 (02) ◽

pp. 101-104 ◽

Cited By ~ 27

Author(s):

Mauro Bianchi ◽

Edda Jotti ◽

Paola Sacerdote ◽

Alberto E. Panerai

Keyword(s):

Immune Responses ◽

T Lymphocyte ◽

Peripheral Blood Mononuclear Cells ◽

Immune Cells ◽

Lymphocyte Proliferation ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Beta Endorphin ◽

T Lymphocyte Proliferation ◽

Blood Mononuclear Cells

We measured beta-endorphin concentrations in peripheral blood mononuclear cells and mitogen-induced T-lymphocyte proliferation in patient who underwent treatment with traditional acupuncture. Traditional acupuncture increased both the concentrations of the opioid in the immune cells and lymphocyte proliferation. Our data are consistent with the hypothesis that traditional acupuncture modulates immune responses in man.

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Truncated PPM1D Prevents Apoptosis in the Murine Thymus and Promotes Ionizing Radiation-Induced Lymphoma

Cells ◽

10.3390/cells9092068 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2068

Author(s):

Andra S. Martinikova ◽

Monika Burocziova ◽

Miroslav Stoyanov ◽

Libor Macurek

Keyword(s):

Dna Damage ◽

Ionizing Radiation ◽

Tumor Formation ◽

Cell Cycle Checkpoints ◽

Negative Regulator ◽

Tumor Suppressor P53 ◽

Mouse Thymus ◽

Truncating Mutation ◽

T Cell Lymphomas ◽

Radiation Induced

Genome integrity is protected by the cell-cycle checkpoints that prevent cell proliferation in the presence of DNA damage and allow time for DNA repair. The transient checkpoint arrest together with cellular senescence represent an intrinsic barrier to tumorigenesis. Tumor suppressor p53 is an integral part of the checkpoints and its inactivating mutations promote cancer growth. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of p53. Although its loss impairs recovery from the G2 checkpoint and promotes induction of senescence, amplification of the PPM1D locus or gain-of-function truncating mutations of PPM1D occur in various cancers. Here we used a transgenic mouse model carrying a truncating mutation in exon 6 of PPM1D (Ppm1dT). As with human cell lines, we found that the truncated PPM1D was present at high levels in the mouse thymus. Truncated PPM1D did not affect differentiation of T-cells in the thymus but it impaired their response to ionizing radiation (IR). Thymocytes in Ppm1dT/+ mice did not arrest in the checkpoint and continued to proliferate despite the presence of DNA damage. In addition, we observed a decreased level of apoptosis in the thymi of Ppm1dT/+ mice. Moreover, the frequency of the IR-induced T-cell lymphomas increased in Ppm1dT/+Trp53+/− mice resulting in decreased survival. We conclude that truncated PPM1D partially suppresses the p53 pathway in the mouse thymus and potentiates tumor formation under the condition of a partial loss of p53 function.

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