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1.
Cell ; 186(6): 1144-1161.e18, 2023 03 16.
Article in English | MEDLINE | ID: mdl-36868219

ABSTRACT

Germinal centers (GCs) that form within lymphoid follicles during antibody responses are sites of massive cell death. Tingible body macrophages (TBMs) are tasked with apoptotic cell clearance to prevent secondary necrosis and autoimmune activation by intracellular self antigens. We show by multiple redundant and complementary methods that TBMs derive from a lymph node-resident, CD169-lineage, CSF1R-blockade-resistant precursor that is prepositioned in the follicle. Non-migratory TBMs use cytoplasmic processes to chase and capture migrating dead cell fragments using a "lazy" search strategy. Follicular macrophages activated by the presence of nearby apoptotic cells can mature into TBMs in the absence of GCs. Single-cell transcriptomics identified a TBM cell cluster in immunized lymph nodes which upregulated genes involved in apoptotic cell clearance. Thus, apoptotic B cells in early GCs trigger activation and maturation of follicular macrophages into classical TBMs to clear apoptotic debris and prevent antibody-mediated autoimmune diseases.


Subject(s)
Germinal Center , Lymph Nodes , Macrophages , Apoptosis , B-Lymphocytes , Lymph Nodes/cytology , Macrophages/cytology , Macrophages/metabolism
2.
Nat Immunol ; 24(9): 1487-1498, 2023 09.
Article in English | MEDLINE | ID: mdl-37474653

ABSTRACT

Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently been shown to control liver-stage infections, we embarked on a messenger RNA (mRNA)-based vaccine strategy to induce liver Trm cells to prevent malaria. Although a standard mRNA vaccine was unable to generate liver Trm or protect against challenge with Plasmodium berghei sporozoites in mice, addition of an agonist that recruits T cell help from type I natural killer T cells under mRNA-vaccination conditions resulted in significant generation of liver Trm cells and effective protection. Moreover, whereas previous exposure of mice to blood-stage infection impaired traditional vaccines based on attenuated sporozoites, mRNA vaccination was unaffected, underlining the potential for such a rational mRNA-based strategy in malaria-endemic regions.


Subject(s)
Malaria Vaccines , Malaria , Animals , Mice , Memory T Cells , Malaria/prevention & control , Liver , Plasmodium berghei/genetics , CD8-Positive T-Lymphocytes
3.
Cell ; 175(2): 530-543.e24, 2018 10 04.
Article in English | MEDLINE | ID: mdl-30220458

ABSTRACT

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.


Subject(s)
Nephritis, Interstitial/virology , Parvovirus/isolation & purification , Parvovirus/pathogenicity , Animals , Australia , Disease Progression , Female , Fibrosis/pathology , Fibrosis/virology , Humans , Kidney/metabolism , Kidney/physiology , Male , Mice , Mice, Inbred C57BL , Nephritis, Interstitial/physiopathology , North America , Parvoviridae Infections/metabolism
4.
Blood ; 143(10): 912-929, 2024 Mar 07.
Article in English | MEDLINE | ID: mdl-38048572

ABSTRACT

ABSTRACT: Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognized, in which brain-infiltrating donor major histocompatibility complex (MHC) class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early after transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients, in which CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signaling after transplant failed to reverse GVHD-induced behavioral changes. Moreover, we observed aberrant behavior in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Mice , Animals , Neuroinflammatory Diseases , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , CD4-Positive T-Lymphocytes , Macrophages/pathology , Receptor Protein-Tyrosine Kinases , Receptors, Colony-Stimulating Factor
5.
Immunity ; 47(2): 374-388.e6, 2017 08 15.
Article in English | MEDLINE | ID: mdl-28813662

ABSTRACT

The liver is positioned at the interface between two routes traversed by pathogens in disseminating infection. Whereas blood-borne pathogens are efficiently cleared in hepatic sinusoids by Kupffer cells (KCs), it is unknown how the liver prevents dissemination of peritoneal pathogens accessing its outer membrane. We report here that the hepatic capsule harbors a contiguous cellular network of liver-resident macrophages phenotypically distinct from KCs. These liver capsular macrophages (LCMs) were replenished in the steady state from blood monocytes, unlike KCs that are embryonically derived and self-renewing. LCM numbers increased after weaning in a microbiota-dependent process. LCMs sensed peritoneal bacteria and promoted neutrophil recruitment to the capsule, and their specific ablation resulted in decreased neutrophil recruitment and increased intrahepatic bacterial burden. Thus, the liver contains two separate and non-overlapping niches occupied by distinct resident macrophage populations mediating immunosurveillance at these two pathogen entry points to the liver.


Subject(s)
Kupffer Cells/physiology , Listeria monocytogenes/immunology , Listeriosis/immunology , Liver/immunology , Macrophages/immunology , Neutrophils/immunology , Peritoneum/microbiology , Animals , Cell Communication , Cell Self Renewal , Host-Pathogen Interactions , Humans , Immunity, Innate , Kupffer Cells/microbiology , Liver/microbiology , Liver/pathology , Macrophages/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/immunology , Neutrophil Infiltration , Peritoneum/pathology
6.
Immunity ; 45(4): 889-902, 2016 10 18.
Article in English | MEDLINE | ID: mdl-27692609

ABSTRACT

In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements probably depend upon development of a broadly protective vaccine. To better understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8+ T cells that expressed the gene signature of tissue-resident memory T (Trm) cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion, or depletion, which may be harnessed to control liver infections or autoimmunity.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , Liver/immunology , Malaria/immunology , Animals , CD8-Positive T-Lymphocytes/parasitology , Culicidae , Dendritic Cells/immunology , Dendritic Cells/parasitology , Hepatocytes/immunology , Hepatocytes/parasitology , Liver/parasitology , Liver Diseases/immunology , Liver Diseases/parasitology , Malaria Vaccines/immunology , Mice , Plasmodium berghei/immunology , Sporozoites/immunology , Sporozoites/parasitology , Vaccination/methods
8.
J Immunol ; 206(12): 2875-2887, 2021 06 15.
Article in English | MEDLINE | ID: mdl-34049970

ABSTRACT

The quality of T cell responses depends on the lymphocytes' ability to undergo clonal expansion, acquire effector functions, and traffic to the site of infection. Although TCR signal strength is thought to dominantly shape the T cell response, by using TCR transgenic CD4+ T cells with different peptide:MHC binding affinity, we reveal that TCR affinity does not control Th1 effector function acquisition or the functional output of individual effectors following mycobacterial infection in mice. Rather, TCR affinity calibrates the rate of cell division to synchronize the distinct processes of T cell proliferation, differentiation, and trafficking. By timing cell division-dependent IL-12R expression, TCR affinity controls when T cells become receptive to Th1-imprinting IL-12 signals, determining the emergence and magnitude of the Th1 effector pool. These findings reveal a distinct yet cooperative role for IL-12 and TCR binding affinity in Th1 differentiation and suggest that the temporal activation of clones with different TCR affinity is a major strategy to coordinate immune surveillance against persistent pathogens.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Mycobacterium bovis/immunology , Receptors, Antigen, T-Cell/immunology , Animals , Cells, Cultured , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic
9.
Cell Mol Life Sci ; 79(8): 443, 2022 Jul 22.
Article in English | MEDLINE | ID: mdl-35867177

ABSTRACT

MiR-181 expression levels increased in hepatocellular carcinoma (HCC) compared to non-cancerous tissues. MiR-181 has been widely reported as a possible driver of tumourigenesis but also acts as a tumour suppressor. In addition, the miR-181 family regulates the development and function of immune and vascular cells, which play vital roles in the progression of tumours. More complicatedly, many genes have been identified as miR-181 targets to mediate the effects of miR-181. However, the role of miR-181 in the development of primary tumours remains largely unexplored. We aimed to examine the function of miR-181 and its vital mediators in the progression of diethylnitrosamine-induced primary liver cancers in mice. The size of liver tumours was significantly reduced by 90% in global (GKO) or liver-specific (LKO) 181ab1 knockout mice but not in hematopoietic and endothelial lineage-specific knockout mice, compared to WT mice. In addition, the number of tumours was significantly reduced by 50% in GKO mice. Whole-genome RNA-seq analysis and immunohistochemistry showed that epithelial-mesenchymal transition was partially reversed in GKO tumours compared to WT tumours. The expression of CBX7, a confirmed miR-181 target, was up-regulated in GKO compared to WT tumours. Stable CBX7 expression was achieved with an AAV/Transposase Hybrid-Vector System and up-regulated CBX7 expression inhibited liver tumour progression in WT mice. Hepatic CBX7 deletion restored the progression of LKO liver tumours. MiR-181a expression was the lowest and CBX7 expression the highest in iClust2 and 3 subclasses of human HCC compared to iClust1. Gene expression profiles of GKO tumours overlapped with low-proliferative peri-portal-type HCCs. Liver-specific loss of miR-181ab1 inhibited primary liver tumour progression via up-regulating CBX7 expression, but tumour induction requires both hepatic and non-hepatic miR-181. Also, miR-181ab1-deficient liver tumours may resemble low-proliferative periportal-type human HCC. miR-181 was increased with liver tumour growth. More miR-181, darker colour and higher shape. CBX7 was very low in pericentral hepatocytes, increased in early liver tumours, but reduced in advanced liver tumours. Its levels were maintained in miR-181 KO liver tumours. In tumours (T), brown (darker is more) represents miR-181, the blue circle (thicker is more) represents CBX7.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , MicroRNAs , Animals , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Polycomb Repressive Complex 1/genetics , Polycomb Repressive Complex 1/metabolism , Up-Regulation/genetics
10.
Immunol Cell Biol ; 100(6): 394-408, 2022 07.
Article in English | MEDLINE | ID: mdl-35718354

ABSTRACT

Portal tracts are key intrahepatic structures where leukocytes accumulate during immune responses. They contain the blood inflow, which includes portal blood from the gut, and lymphatic and biliary outflow of the liver, and as such represent a key interface for potential pathogen entry to the liver. Myeloid cells residing in the interstitium of the portal tract might play an important role in the surveillance or prevention of pathogen dissemination; however, the exact composition and localization of this population has not been explored fully. Our in-depth characterization of portal tract myeloid cells revealed that in addition to T lymphocytes, portal tracts contain a heterogeneous population of MHCIIhigh myeloid cells with potential antigen presenting cell (APC) function. These include a previously unreported subset of CSF1R-dependent CX3CR1+ macrophages that phenotypically and morphologically resemble liver capsular macrophages, as well as the two main dendritic cell subsets (cDC1 and cDC2). These cells are not randomly distributed, but each subset forms interconnected networks intertwined with specific components of the portal tract. The CX3CR1+ cells were preferentially detected along the outer border of the portal tracts, and also in the portal interstitium adjacent to the portal vein, bile duct, lymphatic vessels and hepatic artery. cDC1s abounded along the lymphatic vessels, while cDC2s mostly surrounded the biliary tree. The specific distributions of these discrete subsets predict that they may serve distinct functions in this compartment. Overall, our findings suggest that portal tracts and their embedded cellular networks of myeloid cells form a distinctive lymphoid compartment in the liver that has the potential to orchestrate immune responses in this organ.


Subject(s)
Liver , Macrophages , Dendritic Cells
11.
J Virol ; 93(19)2019 10 01.
Article in English | MEDLINE | ID: mdl-31292249

ABSTRACT

Hepatitis C virus (HCV) is a significant contributor to the global disease burden, and development of an effective vaccine is required to eliminate HCV infections worldwide. CD4+ and CD8+ T cell immunity correlates with viral clearance in primary HCV infection, and intrahepatic CD8+ tissue-resident memory T (TRM) cells provide lifelong and rapid protection against hepatotropic pathogens. Consequently, we aimed to develop a vaccine to elicit HCV-specific CD4+ and CD8+ T cells, including CD8+ TRM cells, in the liver, given that HCV primarily infects hepatocytes. To achieve this, we vaccinated wild-type BALB/c mice with a highly immunogenic cytolytic DNA vaccine encoding a model HCV (genotype 3a) nonstructural protein (NS5B) and a mutant perforin (pVAX-NS5B-PRF), as well as a recombinant adeno-associated virus (AAV) encoding NS5B (rAAV-NS5B). A novel fluorescent target array (FTA) was used to map immunodominant CD4+ T helper (TH) cell and cytotoxic CD8+ T cell epitopes of NS5B in vivo, which were subsequently used to design a KdNS5B451-459 tetramer and analyze NS5B-specific T cell responses in vaccinated mice in vivo The data showed that intradermal prime/boost vaccination with pVAX-NS5B-PRF was effective in eliciting TH and cytotoxic CD8+ T cell responses and intrahepatic CD8+ TRM cells, but a single intravenous dose of hepatotropic rAAV-NS5B was significantly more effective. As a T-cell-based vaccine against HCV should ideally result in localized T cell responses in the liver, this study describes primary observations in the context of HCV vaccination that can be used to achieve this goal.IMPORTANCE There are currently at least 71 million individuals with chronic HCV worldwide and almost two million new infections annually. Although the advent of direct-acting antivirals (DAAs) offers highly effective therapy, considerable remaining challenges argue against reliance on DAAs for HCV elimination, including high drug cost, poorly developed health infrastructure, low screening rates, and significant reinfection rates. Accordingly, development of an effective vaccine is crucial to HCV elimination. An HCV vaccine that elicits T cell immunity in the liver will be highly protective for the following reasons: (i) T cell responses against nonstructural proteins of the virus are associated with clearance of primary infection, and (ii) long-lived liver-resident T cells alone can protect against malaria infection of hepatocytes. Thus, in this study we exploit promising vaccination platforms to highlight strategies that can be used to evoke highly functional and long-lived T cell responses in the liver for protection against HCV.


Subject(s)
Dependovirus/genetics , Drug Carriers , Hepacivirus/immunology , Liver/immunology , T-Lymphocytes/immunology , Viral Nonstructural Proteins/immunology , Viral Vaccines/immunology , Animals , Genetic Vectors , Immunization Schedule , Isoantigens , Mice, Inbred BALB C , Treatment Outcome , Vaccines, DNA/administration & dosage , Vaccines, DNA/immunology , Viral Tropism , Viral Vaccines/administration & dosage
12.
Immunol Cell Biol ; 97(3): 326-339, 2019 03.
Article in English | MEDLINE | ID: mdl-30537346

ABSTRACT

Class Ib major histocompatibility complex (MHC) is an extended family of molecules, which demonstrate tissue-specific expression and presentation of monomorphic antigens. These characteristics tend to imbue class Ib MHC with unique functions. H2-Q10 is potentially one such molecule that is overexpressed in the liver but its immunological function is not known. We have previously shown that H2-Q10 is a ligand for the natural killer cell receptor Ly49C and now, using H2-Q10-deficient mice, we demonstrate that H2-Q10 can also stabilize the expression of Qa-1b. In the absence of H2-Q10, the development and maturation of conventional hepatic natural killer cells is disrupted. We also provide evidence that H2-Q10 is a new high affinity ligand for CD8αα and controls the development of liver-resident CD8αα γδT cells. These data demonstrate that H2-Q10 has multiple roles in the development of immune subsets and identify an overlap of recognition within the class Ib MHC that is likely to be relevant to the regulation of immunity.


Subject(s)
H-2 Antigens/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, Immunologic/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Animals , Biomarkers , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation/genetics , Cell Differentiation/immunology , H-2 Antigens/genetics , H-2 Antigens/metabolism , Immunomodulation/genetics , Immunophenotyping , Killer Cells, Natural/cytology , Ligands , Liver/immunology , Liver/metabolism , Mice , Protein Binding , T-Lymphocyte Subsets/cytology
13.
Diabetologia ; 61(7): 1633-1643, 2018 07.
Article in English | MEDLINE | ID: mdl-29691600

ABSTRACT

AIMS/HYPOTHESIS: Numerous adaptations of the maternal immune system are necessary during pregnancy to maintain immunological tolerance to the semi-allogeneic fetus. Several complications of pregnancy have been associated with dysregulation of these adaptive mechanisms. While gestational diabetes mellitus (GDM) has been associated with upregulation of circulating inflammatory factors linked to innate immunity, polarisation of the adaptive immune system has not been extensively characterised in this condition. We aimed to characterise pro- and anti-inflammatory CD4+ (T helper [Th]) T cell subsets in women with GDM vs women without GDM (of similar BMI), during and after pregnancy, and examine the relationship between CD4+ subsets and severity of GDM. METHODS: This is a prospective longitudinal case-control study of 55 women with GDM (cases) and 65 women without GDM (controls) at a tertiary maternity hospital. Quantification of proinflammatory (Th17, Th17.1, Th1) and anti-inflammatory (regulatory T cell [Treg]) CD4+ T cell subsets was performed on peripheral blood at 37 weeks gestation and 7 weeks postpartum, and correlated with clinical characteristics and measures of blood glucose. RESULTS: Women with GDM had a significantly greater percentage of Th17 (median 2.49% [interquartile range 1.62-4.60] vs 1.85% [1.13-2.98], p = 0.012) and Th17.1 (3.06% [1.30-4.33] vs 1.55% [0.65-3.13], p = 0.006) cells compared with the control group of women without GDM. Women with GDM also had higher proinflammatory cell ratios (Th17:Treg, Th17.1:Treg and Th1:Treg) in pregnancy compared with the control group of women without GDM. In the control group, there was a statistically significant independent association between 1 h glucose levels in the GTT and Th17 cell percentages, and also between 2 h glucose levels and percentage of Th17 cells. The percentage of Th17 cells and the Th17:Treg ratio declined significantly after delivery in women with GDM, whereas this was not the case with the control group of women. Nevertheless, a milder inflammatory phenotype persisted after delivery (higher Th17:Treg ratio) in women with GDM vs women without. CONCLUSIONS/INTERPRETATION: Dysregulation of adaptive immunity supports a novel paradigm of GDM that extends beyond hyperglycaemia and altered innate immunity.


Subject(s)
Diabetes, Gestational/immunology , Inflammation/immunology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology , Adaptive Immunity , Adult , Biomarkers/blood , Blood Glucose/metabolism , Case-Control Studies , Diabetes, Gestational/blood , Diabetes, Gestational/diagnosis , Female , Humans , Immunity, Innate , Inflammation/blood , Inflammation/diagnosis , Longitudinal Studies , Phenotype , Pregnancy , Prospective Studies , Severity of Illness Index , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Regulatory/metabolism
14.
Cancer Immunol Immunother ; 67(4): 563-573, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29289977

ABSTRACT

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4+ T cells were profoundly depleted by ATG, while CD8+ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4+ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4-CCR6- effector/memory CD4+ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4+ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.


Subject(s)
Adrenal Cortex Hormones/pharmacology , Antibodies, Monoclonal/adverse effects , Drug Resistance, Neoplasm , Hepatitis/etiology , Immunotherapy/adverse effects , Melanoma/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , T-Lymphocytes/immunology , Aged , Case-Control Studies , Female , Hepatitis/pathology , Humans , Male , Melanoma/immunology , Melanoma/metabolism , Melanoma/pathology , Middle Aged , Prognosis , T-Lymphocytes/drug effects , T-Lymphocytes/pathology
15.
Immunol Cell Biol ; 95(5): 443-453, 2017 05.
Article in English | MEDLINE | ID: mdl-27899813

ABSTRACT

Liver fibrosis is a progressive pathological process involving inflammation and extracellular matrix deposition. Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a cell surface glycoprotein and serine protease. DPP4 binds to fibronectin, can inactivate specific chemokines, incretin hormone and neuropeptides, and influences cell adhesion and migration. Such properties suggest a pro-fibrotic role for this peptidase but this hypothesis needs in vivo examination. Experimental liver injury was induced with carbon tetrachloride (CCl4) in DPP4 gene knockout (gko) mice. DPP4 gko had less liver fibrosis and inflammation and fewer B cell clusters than wild type mice in the fibrosis model. DPP4 inhibitor-treated mice also developed less liver fibrosis. DNA microarray and PCR showed that many immunoglobulin (Ig) genes and some metabolism-associated transcripts were differentially expressed in the gko strain compared with wild type. CCl4-treated DPP4 gko livers had more IgM+ and IgG+ intrahepatic lymphocytes, and fewer CD4+, IgD+ and CD21+ intrahepatic lymphocytes. These data suggest that DPP4 is pro-fibrotic in CCl4-induced liver fibrosis and that the mechanisms of DPP4 pro-fibrotic action include energy metabolism, B cells, NK cells and CD4+ cells.


Subject(s)
Dipeptidyl Peptidase 4/metabolism , Liver Cirrhosis/enzymology , Liver Cirrhosis/pathology , Liver/enzymology , Liver/injuries , Animals , Carbon Tetrachloride , Cell Line , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Humans , Leukocytes/drug effects , Leukocytes/metabolism , Leukocytes/pathology , Liver/pathology , Liver Cirrhosis/genetics , Mice , Mice, Knockout , Phenotype , Spleen/pathology , Up-Regulation
16.
Proc Natl Acad Sci U S A ; 111(25): E2540-9, 2014 Jun 24.
Article in English | MEDLINE | ID: mdl-24927525

ABSTRACT

CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adenoassociated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions.


Subject(s)
Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , Gene Expression Regulation/immunology , Hepatocytes/immunology , Liver/immunology , Animals , Antigens/genetics , CD8-Positive T-Lymphocytes/cytology , Gene Expression Regulation/genetics , Hepatocytes/cytology , Liver/cytology , Mice , Mice, Knockout
17.
J Hepatol ; 64(6): 1327-38, 2016 06.
Article in English | MEDLINE | ID: mdl-26924452

ABSTRACT

BACKGROUND & AIMS: Acute hepatitis is often mediated by cytotoxic T lymphocytes (CTLs); however, the intrinsic parameters that limit CTL-mediated liver injury are not well understood. METHODS: To investigate whether acute liver damage is limited by molecules that decrease the lifespan or effector function of CTLs, we used a well-characterized transgenic (Tg) mouse model in which acute liver damage develops upon transfer of T cell receptor (TCR) Tg CD8 T cells. Recipient Tg mice received donor TCR Tg T cells deficient for either the pro-apoptotic molecule Bim, which regulates CTL survival, or suppressor of cytokine signaling-1 (SOCS-1), which controls expression of common gamma chain cytokines; the effects of anti-PD-L1 neutralizing antibodies were also assessed. RESULTS: Use of Bim-deficient donor T cells and/or PD-L1 blockade increased the number of intrahepatic T cells without affecting the degree and kinetic of acute hepatitis. In contrast, SOCS-1-deficient T cells induced a heightened, prolonged acute hepatitis caused by their enhanced cytotoxic function and increased expansion. Although they inflicted more severe acute liver damage, SOCS-1-deficient T cells never precipitated chronic hepatitis and became exhausted. CONCLUSIONS: The degree of acute hepatitis is regulated by the function of CD8 T cells, but is not affected by changes in CTL lifespan. Although manipulation of the examined parameters affected acute hepatitis, persistent hepatitis did not ensue, indicating that, in the presence of high intrahepatic antigen load, changes in these factors in isolation were not sufficient to prevent T cell exhaustion and mediate progression to chronic hepatitis.


Subject(s)
Hepatitis/etiology , T-Lymphocytes, Cytotoxic/immunology , Acute Disease , Animals , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/physiology , Bcl-2-Like Protein 11/physiology , Cell Survival , Hepatitis/immunology , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Transgenic , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/physiology , Receptors, Antigen, T-Cell/physiology , Suppressor of Cytokine Signaling 1 Protein/physiology , T-Lymphocytes, Cytotoxic/physiology
19.
J Immunol ; 193(5): 2087-95, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25070847

ABSTRACT

Naive T cell activation is normally restricted to the lymphoid organs, in part because of their limited ability to migrate into the parenchyma of peripheral tissues. The liver vasculature is unique, however, and circulating leukocytes within the hepatic sinusoids have direct access to liver-resident cells, which include an abundant population of Kupffer cells. It is well accepted that recognition of cognate Ag within the liver leads to naive CD8(+) T cell activation in situ, but it is unclear whether the liver also supports naive CD4(+) T cell activation. In this study, we show that naive CD4(+) T cells can be activated to proliferate in the liver when cognate Ag expression is induced in hepatocytes by recombinant adeno-associated viral vectors. Ag-specific retention and activation of naive CD4(+) T cells within the liver are independent of lymphoid tissues but dependent on a clodronate liposome-sensitive population of liver-resident phagocytic cells. To our knowledge, this study provides the first unequivocal evidence that naive CD4(+) T cells can be activated in a nonlymphoid organ. It also gives critical insight into how CD4(+) T cells specific for Ag expressed in the liver are recruited to participate in protective or pathological responses during hepatotropic infections and autoimmune liver disease.


Subject(s)
Autoimmune Diseases/immunology , CD4-Positive T-Lymphocytes/immunology , Kupffer Cells/immunology , Liver Diseases/immunology , Liver/immunology , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/pathology , Bone Density Conservation Agents/pharmacology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Clodronic Acid/pharmacology , Kupffer Cells/pathology , Liposomes , Liver/pathology , Liver Diseases/genetics , Liver Diseases/pathology , Lymphocyte Activation , Mice , Mice, Transgenic
20.
Infect Immun ; 83(4): 1406-17, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25644000

ABSTRACT

Gamma interferon (IFN-γ) drives antiparasite responses and immunopathology during infection with Plasmodium species. Immunity-related GTPases (IRGs) are a class of IFN-γ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used the Plasmodium berghei ANKA (PbA) model in which mice develop experimental cerebral malaria (ECM) to study the roles of IRGM1 and IRGM3 in immunopathology. Induction of mRNA for Irgm1 and Irgm3 was found in the brains and spleens of infected mice at times of peak IFN-γ production. Irgm3-/- but not Irgm1-/- mice were completely protected from the development of ECM, and this protection was associated with the decreased induction of inflammatory cytokines, as well as decreased recruitment and activation of CD8+ T cells within the brain. Although antigen-specific proliferation of transferred CD8+ T cells was not diminished compared to that of wild-type recipients following PbA infection, T cells transferred into Irgm3-/- recipients showed a striking impairment of effector differentiation. Decreased induction of several inflammatory cytokines and chemokines (interleukin-6, CCL2, CCL3, and CCL4), as well as enhanced mRNA expression of type-I IFNs, was found in the spleens of Irgm3-/- mice at day 4 postinfection. Together, these data suggest that protection from ECM pathology in Irgm3-/- mice occurs due to impaired generation of CD8+ effector function. This defect is nonintrinsic to CD8+ T cells. Instead, diminished T cell responses most likely result from defective initiation of inflammatory responses in myeloid cells.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , GTP Phosphohydrolases/immunology , Malaria, Cerebral/immunology , Plasmodium berghei/immunology , Adoptive Transfer , Animals , Antigens, Protozoan/immunology , Brain/immunology , Brain/parasitology , Brain/pathology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/transplantation , Cell Proliferation/genetics , Chemokine CCL2/biosynthesis , Chemokine CCL3/biosynthesis , Chemokine CCL4/biosynthesis , GTP Phosphohydrolases/genetics , GTP-Binding Proteins/genetics , GTP-Binding Proteins/immunology , Inflammation/genetics , Inflammation/immunology , Interferon Type I/biosynthesis , Interferon-gamma/immunology , Interleukin-6/biosynthesis , Malaria, Cerebral/parasitology , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA, Messenger/genetics
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