scholarly journals IL-22 hinders antiviral T cell responses and exacerbates neurological disorders in ZIKV-infected immunocompetent neonatal mice

2020 ◽  
Author(s):  
Yuejin Liang ◽  
Panpan Yi ◽  
Wenjuan Ru ◽  
Zuliang Jie ◽  
Hui Wang ◽  
...  
Keyword(s):  
Weight Loss ◽  
T Cell ◽  
Neurological Disorders ◽  
T Cell Responses ◽  
Host Immunity ◽  
Zikv Infection ◽  
Cell Responses ◽  
The Brain

Abstract Background The Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of neurological disorders and congenital defects. However, host immunity and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays a role in ZIKV infection is unknown. Methods The cellular source of IL-22 was identified in IFNAR−/− mice and WT neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old wild-type (WT) and IL-22−/− mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8+ T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, we infected mouse primary astrocytes in vitro, and characterized the reactive astrocyte phenotype. Human glial cell line was also infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression and viral loads. Results We found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to develop weight loss, staggered steps, bilateral hind limb paralysis, weakness at 10 days post-infection (dpi), and ultimately succumbed to infection at 16–19 dpi. Surprisingly, IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly reduced the incidence of neurological disorders and mortality. ZIKV infection facilitated a neurotoxic polarization of A1-prone astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a marginal effect on glial cells in vitro, IL-22−/− mice mounted more vigorous ZIKV-specific CD8+ T cell responses, which led to a more effective control of ZIKV in the brain. Conclusions Our data revealed a pathogenic role of IL-22 in ZIKV encephalitis.

scholarly journals Studying the immunosuppressive role of indoleamine 2,3-dioxygenase: tryptophan metabolites suppress rat allogeneic T-cell responses in vitro and in vivo

2005 ◽  
Vol 18 (1) ◽  
pp. 95-100 ◽  
Author(s):  
Thomas M. Bauer ◽  
Lucian P. Jiga ◽  
Jing-Jing Chuang ◽  
Marco Randazzo ◽  
Gerhard Opelz ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Cell Responses ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tryptophan Metabolites

scholarly journals The Role of the IL-12 Cytokine Family in Directing T-Cell Responses in Oral Candidosis

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Xiao-Qing Wei ◽  
Helen Rogers ◽  
Michael A. O. Lewis ◽  
David W. Williams
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Treg Cells ◽  
Host Immunity ◽  
Therapeutic Interventions ◽  
Host Recognition ◽  
Cell Responses ◽  
Oral Candidosis ◽  
Opportunistic Fungal Pathogen

Candida albicansis an opportunistic fungal pathogen that normally exists as a harmless commensal in humans. In instances where host debilitation occurs,Candidacan cause a range of clinical infections, and whilst these are primarily superficial, effecting mucosal membranes, systemic infections can develop in severely immunocompromised individuals. The mechanism of host immunity during commensal carriage ofC. albicanshas been intensively studied. In this paper, we present the most recent information concerning host recognition ofC. albicansleading to cytokine production and the subsequent T-cell responses generated in response toC. albicans. Particular focus is given to the role of the IL-12 cytokine family including IL-12, IL-23, IL-27, and IL-35, in host immunity toCandida. T-cells are considered crucial in the regulation of immunity and inflammation. In this regard, the role of Th1/2, helper cells, together with the recently identified Th17 and Treg cells in candidosis will be discussed. Understanding the detailed mechanisms that underlie host immunity toCandidanot only will be of benefit in terms of the infections caused by this organism but could also be exploited in the development of therapeutic interventions for other diseases.

scholarly journals Time elapsed between Zika and dengue virus infections affects antibody and T cell responses

2019 ◽  
Author(s):  
Erick X. Pérez-Guzmán ◽  
Petraleigh Pantoja ◽  
Crisanta Serrano-Collazo ◽  
Mariah A. Hassert ◽  
Alexandra Ortiz-Rosa ◽  
...  
Keyword(s):  
T Cell ◽  
Dengue Virus ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Denv Infection ◽  
Virus Infections ◽  
Zikv Infection ◽  
Cell Responses ◽  
Inflammatory Status

AbstractThe role of Zika virus (ZIKV) immunity on subsequent dengue virus (DENV) infections is relevant to anticipate the dynamics of forthcoming DENV epidemics in areas with previous ZIKV exposure. We study the effect of ZIKV infection with various strains on subsequent DENV immune response after 10 and 2 months of ZIKV infection in rhesus macaques. Our results show that a subsequent DENV infection in animals with early- and middle-convalescent periods to ZIKV do not promote an increase in DENV viremia nor pro-inflammatory status. Previous ZIKV exposure increases the magnitude of the antibody and T cell responses against DENV, and different time intervals between infections alter the magnitude and durability of such responses—more after longer ZIKV pre-exposure. Collectively, we find no evidence of a detrimental effect of ZIKV immunity in a subsequent DENV infection. This supports the implementation of ZIKV vaccines that could also boost immunity against future DENV epidemics.

scholarly journals C-type lectin receptor DCIR contributes to hippocampal injury in acute neurotropic virus infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Melanie Stoff ◽  
Tim Ebbecke ◽  
Malgorzata Ciurkiewicz ◽  
Suvarin Pavasutthipaisit ◽  
Sabine Mayer-Lambertz ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Infection ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Lectin Receptors ◽  
Neurotropic Virus ◽  
Cell Responses ◽  
The Impact ◽  
The Brain

AbstractNeurotropic viruses target the brain and contribute to neurologic diseases. C-type lectin receptors (CLRs) are pattern recognition receptors that recognize carbohydrate structures on endogenous molecules and pathogens. The myeloid CLR dendritic cell immunoreceptor (DCIR) is expressed by antigen presenting cells and mediates inhibitory intracellular signalling. To investigate the effect of DCIR on neurotropic virus infection, mice were infected experimentally with Theiler’s murine encephalomyelitis virus (TMEV). Brain tissue of TMEV-infected C57BL/6 mice and DCIR−/− mice were analysed by histology, immunohistochemistry and RT-qPCR, and spleen tissue by flow cytometry. To determine the impact of DCIR deficiency on T cell responses upon TMEV infection in vitro, antigen presentation assays were utilised. Genetic DCIR ablation in C57BL/6 mice was associated with an ameliorated hippocampal integrity together with reduced cerebral cytokine responses and reduced TMEV loads in the brain. Additionally, absence of DCIR favoured increased peripheral cytotoxic CD8+ T cell responses following TMEV infection. Co-culture experiments revealed that DCIR deficiency enhances the activation of antigen-specific CD8+ T cells by virus-exposed dendritic cells (DCs), indicated by increased release of interleukin-2 and interferon-γ. Results suggest that DCIR deficiency has a supportive influence on antiviral immune mechanisms, facilitating virus control in the brain and ameliorates neuropathology during acute neurotropic virus infection.

scholarly journals Pparα Ablation Suppresses T Cell Responses and Anti-Tumor Immunity By Compromising the Antigen-Presenting Properties of Tumor-Associated Macrophages

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 438-438
Author(s):  
Anthos Christofides ◽  
Carol Cao ◽  
Qi Wang ◽  
Natalia M Tijaro-Ovalle ◽  
Eirini Konstantinidou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Innate Immune ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Responses

Abstract Peroxisome proliferator activated receptors (PPARs) are transcription factors that belong to nuclear hormone superfamily, with three distinct types identified: PPARapha (PPARα), PPARgamma (PPARγ), and PPARbeta/delta (PPARβ/δ). PPARs possess a critical role in the regulation of lipid metabolism, and thus play critical roles in the differentiation and fate of immune cells. PPARα is involved in lipid and carbohydrate metabolism and PPARα agonists, such as fibrates, have been used for the treatment of hypertriglyceridemia and cardiovascular diseases. PPARα has an anti-inflammatory role during infection, and similar to PPARγ, affects the polarization of macrophages. In acute myelogenous leukemia (AML), PPARα mutations correlate with chemoresistance, poor treatment outcomes and unfavorable prognosis. In experimental tumor models, it has been proposed that PPARα agonists might enhance anti-tumor T cell responses during PD-1 blocking immunotherapy. To dissect the mechanistic role of PPARα in tumor immunity, we used mice with global deletion of PPARα and examined tumor growth and profile of the immunological landscape, using various syngeneic tumor models. Significantly larger B16-F10 melanoma and MC-17 fibrosarcoma tumors were observed in PPARα KO mice compared with wild-type control, suggesting that PPARα deletion attenuated the immunological response against cancer. To dissect the role of PPARα in key populations of the innate and adaptive immune system involved in anti-tumor responses, we analyzed the immunological landscape of tumor, tumor draining lymph nodes (TDLN) and spleen, 14-16 days after tumor implantation. Assessment of CD4 + and CD8 + T cells, CD11b +F4/80 + tumor-associated macrophages (TAMs), CD11b +Ly6C hiLy6G - monocytic myeloid derived suppressor cells (M-MDSC), and CD11b +Ly6C loLy6G + polymorphonuclear myeloid derived suppressor cells (PMN-MDSC), by using flow cytometry, showed no quantitative differences between the two experimental groups. Functionally, MDSC from PPARα KO and WT mice showed comparable immunosuppressive properties as determined by suppression assay using splenocytes from OTI transgenic mice. However, PPARα KO TAMs demonstrated a less activated state, as determined by the lower expression levels of MHC-II that is critical for antigen presentation, and CD86 that is critical for T cell costimulation and prevention of T cell anergy and exhaustion. In agreement with these properties of TAMs, CD4 + T cells from TDLN of PPARα KO mice had diminished expression of activation markers, including PD-1, PD-L1 and ICOS, and numerically decreased central memory-like CD4 + T cells (T CM), compared to control tumor bearing mice. Furthermore, CD69, an emerging marker of T cell exhaustion, was significantly upregulated in CD4 + and CD8 + T cells from the TDLN of PPARα KO mice. To determine whether PPARα ablation altered the cell intrinsic properties of myeloid cells and/or T cells resulting in impaired anti-tumor function, we examined in vitro responses of isolated populations. In response to activation via TCR/CD3 and CD28, PPARα deficient T cells had no significant differences in expansion and cytokine production compared to control. In contrast, PPARα deficient Ly6C + monocytes isolated from the bone marrow displayed diminished responses to TLR-mediated signaling as determined by production of IL-6 and TNFα. Our in vitro and in vivo findings reveal a dominant role of PPARα in regulating the fate of innate immune cells thereby altering T cell responses and anti-tumor function. Our findings have implications for the development of new therapeutic approaches to enhance innate immune cell function for the improvement of cancer immunotherapy. Disclosures No relevant conflicts of interest to declare.

Atypical E2F Dependent Dysregulation Of Cell Cycling By Microrna-142 Regulates T-Cell Responses and Experimental Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 136-136 ◽  
Author(s):  
Yaping Sun ◽  
Kay Oravecz-Wilson ◽  
Thomas Saunders ◽  
Ying Wang ◽  
Tomomi Toubai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
T Cell Responses ◽  
Cell Responses ◽  
Cell Cycling

Abstract Noncoding microRNAs (miRs) have recently been linked to immune system function. We investigated the role of miR-142, a hematopoietic specific miR, in regulating T cell responses. To understand its specific function in T cell immunity we utilized homologous recombination technology and generated mutant mice bearing a targeted deletion of the miR-142 gene on the B6 background. The homozygous miR-142 knockout (KO) animals were viable, fertile and showed no apparent developmental anomalies. Thymic analyses of the miR142-/- animals demonstrated no significant differences when compared with WT littermate controls in total thymocytes, early thymic progenitors, DP and DN cells. Bone marrow studies demonstrated similar numbers of LSK+ HSCs while analyses of secondary lymphoid organs (spleen and popliteal lymph nodes) demonstrated similar absolute numbers of naïve T cells (CD44low62L+), memory like T cells (CD44hi62L+CCR7- and CD44hi62L-CCR7- cells), CD4+25+Foxp3+ cells, CD69+VLA4+CD3+ cells and weekly peripheral blood examination demonstrated similar lymphocyte counts as the WT littermates. Functional studies, however, demonstrated that when compared with WT T-cells, the KO T-cells showed significantly slower rate of proliferation by CFSE analyses upon stimulation anti-CD3+ and 28+ antibodies (P<0.003). They showed lower IL-2, IFNγ and IL-17 but greater amount of IL-6 production (P<0.001) and demonstrated greater apoptosis (P<0.02). Cell cycling analyses with flow cytometry demonstrated that a significantly greater percent of the miR142-/- T-cells were in the S and G2 phase (P<0.01) when compared with WT T-cells suggesting altered cell cycling. Similar reduction in proliferation, cytokine secretion by the miR142-/- T-cells was also observed upon in vitro stimulation with allogeneic BALB/c DCs. To determine the in vivo relevance of miR142 deficiency in T cells, we next utilized MHC mismatched B6àBALB/c model of allogeneic BMT. BALB/c animals were lethally irradiated (9Gy) and transplanted on day 0 with 5x106 BM from WT B6 animals along with 2x106 splenic CD90+T cells from the WT or miR142-/- donors. The allogeneic animals that received KO T-cells showed significantly less severe clinical, histopathological GVHD (GI tract on days 7 and 21) and mortality (P<0.02). Analyses of donor T cells on day 7 post-BMT demonstrated reduced expansion and IFNγ secretion (P<0.04) but showed no significant differences in the ratio of Treg:conventional T-cells between the WT and KO T-cell allogeneic recipients. To further confirm the specific role of miR142 deficiency, we next treated the WT animals with miR-142 anatgomir (days 1, 3 and 7) and found that it significantly reduced GVHD mortality (P<0.003). The KO T-cells also reduced GVHD mortality in a MHC matched minor mismatched B6→C3H.sw BMT model demonstrating strain independent effects. To further determine the miR142 specific molecular mechanisms we performed extensive bioinformatic analyses. In light of a defect in T cell cycling in miR142-/- T-cells, we focused on the putative miR142 targets that are known to regulate cell cycling. Two of the three bioinformatic programs suggested the following known regulators of cell cycling, EGR2, DAG, all eight E2F transcription factor family (the typical E2F1-6 and atypical E2F7-8) members as putative targets. We next performed DNA microarray analyses to determine differential gene expression patterns in miR142-/- and WT T cells, which demonstrated an increase in the expression (>15x) of only the atypical E2Fs, namely E2F7 and E2F8, but not in any of the other above predicted cell cycle regulating molecules. The increase in the expression of the atypical E2Fs in the miR142-/- T-cells was next confirmed by PCR analyses at baseline (unstimulated) and also sequentially at 6, 12, 24 and 48 hours following in vitro stimulation. Knockdown of E2F7 and E2F8 in miR142-/- T cells with sh-RNA rescued their proliferative responses and corrected the cell cycling defects to the levels comparable to WT T-cells, thus demonstrating that the atypical E2F7 and 8 are critical for miR-142 mediated regulation of T cells. Thus our data show (a) generation of a novel miR142 knockout mouse (b) demonstrate that miR142 regulates T cell responses in vitro and in vivo by targeting atypical E2Fs and (c) suggest that targeting miR142 in vivo with its antagomir might be a novel therapeutic strategy for regulating GVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Neutrophil subtypes shape HIV-specific CD8 T-cell responses after vaccinia virus infection

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Mauro Di Pilato ◽  
Miguel Palomino-Segura ◽  
Ernesto Mejías-Pérez ◽  
Carmen E. Gómez ◽  
Andrea Rubio-Ponce ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
Adaptive Immune System ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Adaptive Immune

AbstractNeutrophils are innate immune cells involved in the elimination of pathogens and can also induce adaptive immune responses. Nα and Nβ neutrophils have been described with distinct in vitro capacity to generate antigen-specific CD8 T-cell responses. However, how these cell types exert their role in vivo and how manipulation of Nβ/Nα ratio influences vaccine-mediated immune responses are not known. In this study, we find that these neutrophil subtypes show distinct migratory and motility patterns and different ability to interact with CD8 T cells in the spleen following vaccinia virus (VACV) infection. Moreover, after analysis of adhesion, inflammatory, and migration markers, we observe that Nβ neutrophils overexpress the α4β1 integrin compared to Nα. Finally, by inhibiting α4β1 integrin, we increase the Nβ/Nα ratio and enhance CD8 T-cell responses to HIV VACV-delivered antigens. These findings provide significant advancements in the comprehension of neutrophil-based control of adaptive immune system and their relevance in vaccine design.

Sign in / Sign up

Export Citation Format

Share Document