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Project description:Targeting BMI-1 in B cells restores effective humoral immune responses and controls chronic viral infection
| PRJNA685814 | ENA
Project description:Multiple inhibitory molecules create a profoundly immunuosuppressive environment during chronic viral infections in humans and mice. Therefore, eliciting effective immunity in this context represents a challenge. Here, we report that during a murine chronic viral infection, interleukin-6 (IL-6) was produced by irradiation-resistant cells in a biphasic manner, with late IL-6 being absolutely essential for viral control. The underlying mechanism involved IL-6 signaling on virus-specific CD4 T cells that caused up-regulation of the transcription factor Bcl6 and enhanced T follicular helper cell responses at late, but not early, stages of chronic viral infection. This resulted in escalation of germinal center reactions and improved antibody responses. Our results uncover an antiviral strategy that helps to safely resolve a persistent infection in vivo.
| S-EPMC3388900 | biostudies-literature
Project description:Immunological checkpoints, such as the inhibitory CD200 receptor (CD200R), play a dual role in balancing the immune system during microbial infection. On the one hand these inhibitory signals prevent excessive immune mediated pathology but on the other hand they may impair clearance of the pathogen. We studied the influence of the inhibitory CD200-CD200R axis on clearance and pathology in two different virus infection models. We find that lack of CD200R signaling strongly enhances type I interferon (IFN) production and viral clearance and improves the outcome of mouse hepatitis corona virus (MHV) infection, particularly in female mice. MHV clearance is known to be dependent on Toll like receptor 7 (TLR7)-mediated type I IFN production and sex differences in TLR7 responses previously have been reported for humans. We therefore hypothesize that CD200R ligation suppresses TLR7 responses and that release of this inhibition enlarges sex differences in TLR7 signaling. This hypothesis is supported by our findings that in vivo administration of synthetic TLR7 ligand leads to enhanced type I IFN production, particularly in female Cd200(-/-) mice and that CD200R ligation inhibits TLR7 signaling in vitro. In influenza A virus infection we show that viral clearance is determined by sex but not by CD200R signaling. However, absence of CD200R in influenza A virus infection results in enhanced lung neutrophil influx and pathology in females. Thus, CD200-CD200R and sex are host factors that together determine the outcome of viral infection. Our data predict a sex bias in both beneficial and pathological immune responses to virus infection upon therapeutic targeting of CD200-CD200R.
| S-EPMC3355091 | biostudies-literature
Project description:Functional exhaustion of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T cell dysfunction are not well understood. Epigenetics plays an important role in the control of T cell development, differentiation, and function. To examine if epigenetics also plays a role in T cell exhaustion, we analyzed chromatin remodeling in CD8(+) T cells from mice with chronic lymphocytic choriomeningitis virus infection. We observed downregulation of diacetylated histone H3 in both virus-specific and total CD8(+) T cells, and functional defects not only in virus-specific CD8(+) T cells but also within the total CD8(+) T cell population. In vitro treatment of these exhausted CD8(+) T cells with histone deacetylase inhibitors restored diacetylated histone H3 levels, and improved their immune functions. Upon adoptive transfer, these treated CD8(+) T cells developed into functional memory T cells in vivo that enhanced protective immunity. These results define a role of epigenetics in T cell exhaustion and suggest epigenetic manipulation as a novel molecular therapy to restore immune functions.
| S-EPMC4435497 | biostudies-literature
Project description:Chronic immune activation, immunosuppression, and T cell exhaustion are hallmarks of HIV infection, yet the mechanisms driving these processes are unclear. Chronic activation can be a driving force in immune exhaustion, and type I interferons (IFN-I) are emerging as critical components underlying ongoing activation in HIV infection. Here, we have tested the effect of blocking IFN-I signaling on T cell responses and virus replication in a murine model of chronic HIV infection. Using HIV-infected humanized mice, we demonstrated that in vivo blockade of IFN-I signaling during chronic HIV infection diminished HIV-driven immune activation, decreased T cell exhaustion marker expression, restored HIV-specific CD8 T cell function, and led to decreased viral replication. Antiretroviral therapy (ART) in combination with IFN-I blockade accelerated viral suppression, further decreased viral loads, and reduced the persistently infected HIV reservoir compared with ART treatment alone. Our data suggest that blocking IFN-I signaling in conjunction with ART treatment can restore immune function and may reduce viral reservoirs during chronic HIV infection, providing validation for IFN-I blockade as a potential therapy for HIV infection.
| S-EPMC5199686 | biostudies-literature
Project description:Persistent viral infections subvert key elements of adaptive immunity. To compare germinal center (GC) B cell responses in chronic and acute lymphocytic choriomeningitis virus infection, we exploit activation-induced deaminase (AID) fate-reporter mice and perform adoptive B cell transfer experiments. Chronic infection yields GC B cell responses of higher cellularity than acute infections do, higher memory B cell and antibody secreting cell output for longer periods of time, a better representation of the late B cell repertoire in serum immunoglobulin, and higher titers of protective neutralizing antibodies. GC B cells of chronically infected mice are similarly hypermutated as those emerging from acute infection. They efficiently adapt to viral escape variants and even in hypermutation-impaired AID mutant mice, chronic infection selects for GC B cells with hypermutated B cell receptors (BCRs) and neutralizing antibody formation. These findings demonstrate that, unlike for CD8+ T cells, chronic viral infection drives a functional, productive, and protective GC B cell response.
| S-EPMC6996002 | biostudies-literature
Project description:Norepinephrine is a key sympathetic neurotransmitter, which acts to suppress CD8 + T cell cytokine secretion and lytic activity by signaling through the β2-adrenergic receptor (ADRB2). Although ADRB2 signaling is considered generally immunosuppressive, its role in regulating the differentiation of effector T cells in response to infection has not been investigated. Using an adoptive transfer approach, we compared the expansion and differentiation of wild type (WT) to Adrb2-/- CD8 + T cells throughout the primary response to vesicular stomatitis virus (VSV) infection in vivo. We measured the dynamic changes in transcriptome profiles of antigen-specific CD8 + T cells as they responded to VSV. Within the first 7 days of infection, WT cells out-paced the expansion of Adrb2-/- cells, which correlated with reduced expression of IL-2 and the IL-2Rα in the absence of ADRB2. RNASeq analysis identified over 300 differentially expressed genes that were both temporally regulated following infection and selectively regulated in WT vs Adrb2-/- cells. These genes contributed to major transcriptional pathways including cytokine receptor activation, signaling in cancer, immune deficiency, and neurotransmitter pathways. By parsing genes within groups that were either induced or repressed over time in response to infection, we identified three main branches of genes that were differentially regulated by the ADRB2. These gene sets were predicted to be regulated by specific transcription factors involved in effector T cell development, such as Tbx21 and Eomes. Collectively, these data demonstrate a significant role for ADRB2 signaling in regulating key transcriptional pathways during CD8 + T cells responses to infection that may dramatically impact their functional capabilities and downstream memory cell development.
| S-EPMC9362915 | biostudies-literature
Project description:Periodontal disease is a dominant global bacterial infection that increases with ageing. AIM:This report focuses on host adaptive immune responses in periodontitis. While experimental models and humans diagnosed with periodontitis demonstrate an antigenic specificity for particular oral bacteria, we have a limited understanding of (i) how ageing affects the adaptive immune responses to these bacteria that chronically colonize the oral cavity for decades prior to disease expression and (ii) how the magnitude and specificity of the response interface with pathogens that emerge within the bacterial ecology during exacerbations of disease. MATERIALS AND METHODS:Serum antibody levels to a group of pathogenic and commensal oral bacteria were measured in a population of individuals from 21 to 74 years of age, stratified based on clinical status of the periodontium, smoking and sex. RESULTS:Clinical parameters were not significantly different within health, gingivitis or periodontitis groups related to age. Antibody to oral pathogens and commensals was similar in different age groups in each of the clinical categories, with no age correlation noted in the periodontitis patients. CONCLUSIONS:The adaptive immune responses to oral bacteria that chronically colonize the oral cavity appear generally unaffected by age, but clearly are linked to the extent of disease.
| S-EPMC5992058 | biostudies-literature
Project description:Chronic infections are characterized by the inability to eliminate the persisting pathogen and often associated with functional impairment of virus-specific T-cell responses. Costimulation through Glucocorticoid-induced TNFR-related protein (GITR) can increase survival and function of effector T cells. Here, we report that constitutive expression of GITR-ligand (GITRL) confers protection against chronic lymphocytic choriomeningitis virus (LCMV) infection, accelerating recovery without increasing pathology. Rapid viral clearance in GITRL transgenic mice coincided with increased numbers of poly-functional, virus-specific effector CD8+ T cells that expressed more T-bet and reduced levels of the rheostat marker PD-1. GITR triggering also boosted the helper function of virus-specific CD4 T cells already early in the infection, as was evidenced by increased IL-2 and IFNγ production, and more expression of CD40L and T-bet. Importantly, CD4-depletion experiments revealed that the expanded pool of virus-specific effector CD8 T cells and the ensuing viral clearance in LCMV-infected GITRL tg mice was entirely dependent on CD4 T cells. We found no major differences for NK cell and regulatory T cell responses, whereas the humoral response to the virus was increased in GITRL tg mice, but only in the late phase of the infection when the virus was almost eradicated. Based on these findings, we conclude that enhanced GITR-triggering mediates its protective, anti-viral effect on the CD8 T cell compartment by boosting CD4 T cell help. As such, increasing costimulation through GITR may be an attractive strategy to increase anti-viral CTL responses without exacerbating pathology, in particular to persistent viruses such as HIV and HCV.
| S-EPMC4349659 | biostudies-literature
Project description:Acute or chronic viral infections can lead to generalized immunosuppression. Several mechanisms, such as immunopathology of CD8(+) T cells, inhibitory receptors, or regulatory T (Treg) cells, contribute to immune dysfunction. Moreover, patients with chronic viral infections usually do not respond to vaccination, a finding that has not been previously explained. Recently, we reported that CD169(+) macrophages enforce viral replication, which is essential for guaranteeing antigen synthesis and efficient adaptive immune responses. In the present study, we used a chronic lymphocytic choriomeningitis virus infection mouse model to determine whether this mechanism is affected by chronic viral infection, which may impair the activation of adaptive immunity. We found that enforced viral replication of a superinfecting virus is completely blunted in chronically infected mice. This absence of enforced viral replication in CD169(+) macrophages is not explained by CD8(+) T-cell-mediated immunopathology but rather by prolonged IFN-I responses. Consequently, the absence of viral replication impairs both antigen production and the adaptive immune response against the superinfecting virus. These findings indicate that chronic infection leads to sustained IFN-I action, which is responsible for the absence of an antiviral immune response against a secondary viral infection.
| S-EPMC5063111 | biostudies-literature