Restoration of type I interferon signaling in intrahepatically primed CD8+ T cells promotes functional differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE159748 | GEO | 2021/02/09
REPOSITORIES: GEO
Similar Datasets
Project description:Reversing CD8+ T cell dysfunction is crucial in therapeutic approaches to eliminate chronic hepatitis B virus (HBV) infection. However, the specific molecular targets for achieving this goal are not fully understood. In this study, we conducted a comprehensive analysis of the co-signaling receptors induced during hepatocellular priming and examined the trajectory and long-term fate of dysfunctional HBV-specific CD8+ T cells. Our findings demonstrate that early during intrahepatic priming, HBV-specific CD8+ T cells selectively upregulate co-inhibitory receptors PD-1, CTLA-4, and LAG-3, as well as co-stimulatory receptors OX40, 4-1BB, and ICOS. While blocking the co-inhibitory receptors had no significant impact, activating 4-1BB and OX40, but not ICOS, transformed these cells into potent antiviral effectors. Prolonged antigenic stimulation of intrahepatically-primed dysfunctional T cells led to the development of a self-renewing, long-lived, heterogeneous population with a unique transcriptional profile that only partially overlaps with other forms of T cell hyporesponsiveness. This population consists of a dysfunctional progenitor or stem-like (TSL) population and two distinct dysfunctional tissue-resident memory (TRM) cell populations, which are hierarchically related. While 4-1BB expression is maintained across all populations, OX40 expression is limited to TSL cells. At later stages, only stimulation of 4-1BB, not OX40, conferred antiviral activity to HBV-specific CD8+ T cells. These findings highlight the therapeutic potential of co-signaling receptor modulation for chronic HBV infection and suggest that targeting all dysfunctional tissue-resident T cells, rather than solely the stem-like precursors, represents a promising strategy, distinguishing it from other conditions characterized by chronic antigenic stimulation.
2024-06-19 | GSE240036 | GEO
Project description:Reversing CD8+ T cell dysfunction is crucial in therapeutic approaches to eliminate chronic hepatitis B virus (HBV) infection. However, the specific molecular targets for achieving this goal are not fully understood. In this study, we conducted a comprehensive analysis of the co-signaling receptors induced during hepatocellular priming and examined the trajectory and long-term fate of dysfunctional HBV-specific CD8+ T cells. Our findings demonstrate that early during intrahepatic priming, HBV-specific CD8+ T cells selectively upregulate co-inhibitory receptors PD-1, CTLA-4, and LAG-3, as well as co-stimulatory receptors OX40, 4-1BB, and ICOS. While blocking the co-inhibitory receptors had no significant impact, activating 4-1BB and OX40, but not ICOS, transformed these cells into potent antiviral effectors. Prolonged antigenic stimulation of intrahepatically-primed dysfunctional T cells led to the development of a self-renewing, long-lived, heterogeneous population with a unique transcriptional profile that only partially overlaps with other forms of T cell hyporesponsiveness. This population consists of a dysfunctional progenitor or stem-like (TSL) population and two distinct dysfunctional tissue-resident memory (TRM) cell populations, which are hierarchically related. While 4-1BB expression is maintained across all populations, OX40 expression is limited to TSL cells. At later stages, only stimulation of 4-1BB, not OX40, conferred antiviral activity to HBV-specific CD8+ T cells. These findings highlight the therapeutic potential of co-signaling receptor modulation for chronic HBV infection and suggest that targeting all dysfunctional tissue-resident T cells, rather than solely the stem-like precursors, represents a promising strategy, distinguishing it from other conditions characterized by chronic antigenic stimulation.
2024-06-19 | GSE263460 | GEO
Project description:CD4+ T cell help is critical for optimal CD8+ T cell expansion after priming in many experimental systems. However, a role for CD4+ T cells in regulating the initial steps of CD8+ T cell effector differentiation is not well established. Here we demonstrate that absence of CD4+ T cells at the time of replication-incompetent adenovirus vector immunization of C57BL/6 mice led to immediate CD8+ T cell dysfunction characteristic of exhaustion at the first detectable timepoints as well as impaired expansion of antigen-specific CD8+ T cells. The absence of CD4+ T cell help resulted in antigen-specific CD8+ T cells that had reduced ex vivo cytotoxicity and decreased capacity to produce IFN-γ and TNF-α. CD8+ T cells primed in the absence of CD4+ T cells expressed elevated levels of the inhibitory receptors PD-1, LAG-3, and Tim-3, and these cells exhibited transcriptomic exhaustion profiles by gene set enrichment analysis. This dysfunctional state was imprinted within 3 days of immunization and could not be reversed by provision of CD4+ T cell help after priming. Partial rescue of unhelped CD8+ T cell expansion and effector differentiation could be achieved by PD-1 pathway blockade or recombinant IL-2 administration. This study identifies a novel, previously undescribed role of CD4+ T cells to prevent immediate dysfunction and features of exhaustion in CD8+ T cells following antigen priming. Splenic AL11-specific CD8 T cells from mice immunized with Ad5HVR48(1-7)-SIV Gag and treated with anti-CD4 antibody or not were purified by FACS on day 14 post-immunization
2016-07-01 | E-GEOD-73001 | biostudies-arrayexpress
Project description:Background and Aims: Chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) and is a serious health problem in China, East Asia, and North African countries. Effective treatment of HBV-related HCC is currently unavailable. This study evaluated the therapeutic potential of TIGIT blockade in HBV-related HCC. Approach and Results: A mouse model of spontaneous HBV-related HCC was generated by replacing wild-type hepatocytes with HBsAg+ hepatocytes (namely HBs-HepR mice). The tumors in HBs-HepR mice were inflammation-associated HCC, similar to HBV-related HCC in patients, which was distinguished from other HCC mouse models, such as diethylnitrosamine (DEN)-induced HCC, Tak1-knockout-induced HCC, HCC in stelic animal model (STAM), or nonalcoholic steatohepatitis (NASH)-induced HCC. HCC in HBs-HepR mice was characterized by an increased number of CD8+T cells whereas the production of IL-2, TNF-α, and IFN-γ by intrahepatic CD8+T cells was decreased. Increased expression of TIGIT on CD8+T cells was responsible for functional exhaustion. The therapeutic effect of TIGIT blockade was investigated at the early and middle stages of HCC progression in HBs-HepR mice. TIGIT blockade reinvigorated intrahepatic CD8+T cells with increased TNF-α and IFN-γ production and an increased number of CD8+T cells in tumors, thereby slowing the development of HCC in HBs-HepR mice. Blocking PD-L1 did not show direct therapeutic effects or synergize with TIGIT blockade. Conclusions: Blockade of TIGIT alone enhanced the anti-tumor activity of CD8+T cells during the progression of HBV-related HCC in a spontaneous HCC mouse model.
2022-12-31 | GSE209856 | GEO
Project description:CD4+ T cell help is critical for optimal CD8+ T cell expansion after priming in many experimental systems. However, a role for CD4+ T cells in regulating the initial steps of CD8+ T cell effector differentiation is not well established. Here we demonstrate that absence of CD4+ T cells at the time of replication-incompetent adenovirus vector immunization of C57BL/6 mice led to immediate CD8+ T cell dysfunction characteristic of exhaustion at the first detectable timepoints as well as impaired expansion of antigen-specific CD8+ T cells. The absence of CD4+ T cell help resulted in antigen-specific CD8+ T cells that had reduced ex vivo cytotoxicity and decreased capacity to produce IFN-γ and TNF-α. CD8+ T cells primed in the absence of CD4+ T cells expressed elevated levels of the inhibitory receptors PD-1, LAG-3, and Tim-3, and these cells exhibited transcriptomic exhaustion profiles by gene set enrichment analysis. This dysfunctional state was imprinted within 3 days of immunization and could not be reversed by provision of CD4+ T cell help after priming. Partial rescue of unhelped CD8+ T cell expansion and effector differentiation could be achieved by PD-1 pathway blockade or recombinant IL-2 administration. This study identifies a novel, previously undescribed role of CD4+ T cells to prevent immediate dysfunction and features of exhaustion in CD8+ T cells following antigen priming.
2016-07-01 | GSE73001 | GEO
Project description:The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg or/and young ages, is still unresolved for lacking surrogate models. Here, we generated a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrated that human IFN stimulated a similar gene expression profile of huIFNAR peripheral blood mononuclear cells (PBMC) to what in human PBMCs, supporting the representativeness of the novel mouse model in functionally analyzing human IFN in vivo. Next, we revealed a markedly tissue-specific gene expression atlas against human IFN treatment in the multiple organs less appreciated in healthy humans in vivo. Finally, using the AAV-HBV model, we test the antiviral effects of human interferon in this mouse. Fifteen-week human PEG-IFNα2 treatment significantly reduced HBsAg and HBeAg and even achieved HBsAg seroconversion. We observed that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon might be critical for HBsAg suppression. In conclusion, our novel huIFNAR mouse can authentically respond to human Interferon stimulation, providing a novel platform to study interferon function in vivo. The PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieved HBsAg seroconversion in some mice.
2023-09-24 | GSE236814 | GEO
Project description:The expansion, trafficking and functional effectiveness of adoptively transferred CD8+ T-cells play a critical role in mediating effective anti-tumor immunity. However, the mechanisms which program the highly proliferative and functional state of CD8+ T-cells are not completely understood. We hypothesized that IL-12, a cytokine commonly induced by TLR activation, could enhance T-cell priming by altering responsiveness to antigen and cytokines. Priming of tumor specific CD8+ T-cells in the presence of IL-12 induced the acquisition of a 'polyfunctional' effector response and increased the generation of memory cells. Moreover, IL-12 priming also promoted high levels of the IL-2 receptor alpha-chain (CD25) and robust IL-2 mediated activation of STAT5. This sensitivity to IL-2 translated into enhanced in vivo proliferation of adoptively transferred CD8+ T-cells. Furthermore, real-time, in vivo imaging of T-cell trafficking confirmed the ability of IL-12 priming to drive in vivo proliferation. IL-12 priming enhanced the anti-tumor function of adoptively transferred cells by reducing established subcutaneous tumor burden, and significantly increasing survival in an established intracranial tumor model. Finally, IL-12 priming of human PBMCs generates tumor specific T-cells phenotypically and functionally similar to IL-12 primed Pmel-1 T-cells. These results highlight IL-12 as an important mediator of CD8+ T-cell effector function and anti-tumor immunity. We primed Pmel-1 TCR transgenic CD8+ T-cells with cognate antigen and either IL-2 or IL-12 and compared their gene expression profiles. This was used to identify pathways or genes necessary for anti-tumor activity in vivo. RNA was isolated from Pmel-1 T-cells primed with antigen and cytokine for 6 days and hybridized to Affymetrix arrays.
2010-10-19 | E-GEOD-22443 | biostudies-arrayexpress
Project description:Hepatitis B virus (HBV) infection is a risk of developing fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. Although HBV elimination requires complete elimination of covalently closed circular DNA (cccDNA), its treatment has not been established. Interferon (IFN) -γ, a type ⅠⅠ IFN, is produced by intrahepatic cytotoxic T lymphocytes and has the noncytolytic antiviral potential. However, the mechanism by which IFN-γ regulates HBV infection in hepatocytes has not been fully elucidated. In this study, to replicate the HBV infection and monitor the amount of cccDNA, we developed an in vitro HBV infection assay system with primary hepatocytes and examined the molecules and signaling pathways. IFN-γ suppressed both HBV propagation and transcription to the same extent as IFN-α. RNA microarray analysis revealed that IFN-γ stimulation induced not only IFN-γ but also IFN-α signaling activation and regulated HBV cccDNA. Moreover, the HBV production was reduced by IFN-γ through JAK-STAT signaling and interferon stimulated genes such as OAS2 and APOBEC3G. Taken together, these results demonstrate that IFN-γ suppresses both HBV propagation and transcription by activating specific intracellular signaling pathways in hepatocytes and suggests the future application of this particular signaling pathways or genes for the complete elimination of HBV.
2019-10-01 | GSE132628 | GEO
Project description:Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Here we examined the antigen specificities of HCC-infiltrating T cells and their relevance to tumor control. Using highly multiplexed peptide-MHC tetramer staining of unexpanded cells from blood, liver and tumor tissues from 46 HCC patients, we detected 91 different antigen-specific CD8+ T cell populations targeting HBV, neoantigen, tumor-associated and disease-unrelated antigens. Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1-low and TOX-low, despite being clonally expanded. High frequencies of intratumoral terminally exhausted T cells was uncommon. Patients with tumor-infiltrating HBV-specific CD8+ Trm cells exhibited longer-term relapse-free survival. Thus, non-terminally exhausted HBV-specific CD8+ Trm cells show hallmarks of active involvement and effective antitumor response, implying that these cells could be harnessed for therapeutic purposes.
2021-04-21 | GSE172400 | GEO
Project description:Defective HBV-specific CD8+ T cells are believed to contribute to a chronic stage of the disease. To increase the understanding of the defective HBV-specific CD8+ T cell response, gene expression in HBV-specific CD8+ T cells were compared with that in HCV- and CMV-specific CD8+ T cells. Tetramer specific CD8+ T cells from chronic HBV or HCV-infected patients and one healthy individual were sorted by flow cytometry. Cells not specific for the particular tetramer were included as controls. Cells were frozen until use. RNA was extracted and then amplified and converted to cDNA before hybridization to Affymetrix microarrays.
2015-08-31 | E-GEOD-60552 | biostudies-arrayexpress