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1.
Sci Rep ; 9(1): 9515, 2019 07 02.
Article in English | MEDLINE | ID: mdl-31266981

ABSTRACT

Most studies in type 1 diabetes (T1D) have focused on the loss of the pancreatic beta-cell population. However, despite the involvement of the alpha-cell in the aetiology and complications of T1D, little is known about the regulation of the pancreatic alpha-cell mass in this disease. The need for a better understanding of this process is further emphasized by recent findings suggesting that alpha-cells may constitute a potential reservoir for beta-cell regeneration. In this study, we characterized the pancreatic alpha-cell mass and its regulatory processes in the transgenic RIP-B7.1 mice model of experimental autoimmune diabetes (EAD). Diabetic mice presented insulitis, hyperglycaemia, hypoinsulinemia and hyperglucagonemia along with lower pancreatic insulin content. While alpha-cell mass and pancreatic glucagon content were preserved at the early-onset of EAD, both parameters were reduced in the advanced phase. At both stages, alpha-cell size, proliferation and ductal neogenesis were up-regulated, whereas apoptosis was almost negligible. Interestingly, we found an increase in the proportion of glucagon-containing cells positive for insulin or the beta-cell transcription factor PDX1. Our findings suggest that pancreatic alpha-cell renewal mechanisms are boosted during the natural course of EAD, possibly as an attempt to maintain the alpha-cell population and/or to increase beta-cell regeneration via alpha-cell transdifferentiation.


Subject(s)
Diabetes Mellitus, Experimental/pathology , Animals , B7-1 Antigen/deficiency , B7-1 Antigen/genetics , Cell Proliferation , Cell Transdifferentiation , Diabetes Mellitus, Experimental/complications , Disease Models, Animal , Glucagon/analysis , Glucagon/metabolism , Glucagon-Secreting Cells/cytology , Glucagon-Secreting Cells/metabolism , Homeodomain Proteins/metabolism , Hyperglycemia/complications , Hyperglycemia/pathology , Insulin/analysis , Insulin/blood , Mice , Mice, Inbred C57BL , Mice, Transgenic , Trans-Activators/metabolism
2.
Eur J Immunol ; 45(1): 214-24, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25329762

ABSTRACT

Neonates rely on their innate immune system. Resident tissue macrophages are considered to be initiators and regulators of the innate immune response and thus, appear to be especially important to neonates. We hypothesized that the phenotype and function of neonatal tissue macrophages differ from their adult counterparts. Peritoneal macrophages from neonatal (<24 h) and adult (6 weeks old) C57BL/6J mice were isolated and analyzed by high-content chipcytometry. After stimulation for 6 h with LPS (0, 1, 10, 100 ng/mL), macrophage transcriptome was analyzed by microarray and cytokine release was measured using multiparametric bead assays. Antigen presenting capacity was compared by T-cell stimulation assays. We observed that neonatal murine peritoneal macrophages are characterized by selective lack of expression of F4/80, MHC class II, and costimulatory molecules (CD80, CD86). Furthermore, we found differences in the transcriptome between neonatal and adult macrophages, unstimulated and after LPS stimulation. Although neonatal macrophages showed a significantly increased secretion of proinflammatory cytokines upon LPS stimulation, their potential to induce T-cell proliferation was significantly reduced. In conclusion, we observed a distinct phenotype of the neonatal macrophage population. The specific functions of this macrophage population could help to understand the excessive inflammatory reactions observed in the very young.


Subject(s)
Aging/immunology , Immunity, Innate , Macrophages, Peritoneal/immunology , T-Lymphocytes/immunology , Transcriptome/immunology , Animals , Animals, Newborn , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , B7-1 Antigen/deficiency , B7-1 Antigen/genetics , B7-1 Antigen/immunology , B7-2 Antigen/deficiency , B7-2 Antigen/genetics , B7-2 Antigen/immunology , Cell Proliferation , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Immunophenotyping , Lipopolysaccharides/pharmacology , Macrophage Activation/drug effects , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/drug effects , Mice , Mice, Inbred C57BL , Phenotype , Primary Cell Culture , T-Lymphocytes/cytology , T-Lymphocytes/drug effects
3.
J Immunol ; 193(3): 1223-32, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24951814

ABSTRACT

Adenoviral vectors have long been forerunners in the development of effective CD8 T cell-based vaccines; therefore, it is imperative that we understand the factors controlling the induction of robust and long-lasting transgene-specific immune responses by these vectors. In this study, we investigated the organ sites, molecules, and cell subsets that play a critical role in the priming of transgene-specific CD8 T cells after vaccination with a replication-deficient adenoviral vector. Using a human adenovirus serotype 5 (Ad5) vector and genetically engineered mice, we found that CD8(+) and/or CD103(+) dendritic cells in the draining lymph node played a critical role in the priming of Ad5-induced CD8 T cell responses. Moreover, we found that CD80/86, but not CD28, was essential for efficient generation of both primary effectors and memory CD8 T cells. Interestingly, the lack of CD28 expression resulted in a delayed primary response, whereas memory CD8 T cells generated in CD28-deficient mice appeared almost normal in terms of both phenotype and effector cytokine profile, but they exhibited a significantly reduced proliferative capacity upon secondary challenge while retaining immediate in vivo effector capabilities: in vivo cytotoxicity and short-term in vivo protective capacity. Overall, our data point to an absolute requirement for professional APCs and the expression of the costimulatory molecules CD80/86 for efficient CD8 T cell priming by adenoviral vectors. Additionally, our results suggest the existence of an alternative receptor for CD80/86, which may substitute, in part, for CD28.


Subject(s)
Adenovirus Infections, Human/prevention & control , Adenoviruses, Human/immunology , B7-1 Antigen/deficiency , B7-2 Antigen/deficiency , CD28 Antigens/deficiency , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Genetic Engineering , Adenovirus Infections, Human/genetics , Adenoviruses, Human/genetics , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Antigen-Presenting Cells/virology , B7-1 Antigen/genetics , B7-2 Antigen/genetics , CD28 Antigens/genetics , CD28 Antigens/metabolism , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , Dendritic Cells/metabolism , Dendritic Cells/virology , Female , Genetic Vectors/administration & dosage , Genetic Vectors/immunology , Humans , Ligands , Lymphocytic choriomeningitis virus/genetics , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Vaccination
4.
Cell Immunol ; 285(1-2): 69-75, 2013.
Article in English | MEDLINE | ID: mdl-24099792

ABSTRACT

B7.1 and B7.2 are homologous costimulatory molecules expressed predominantly on antigen-presenting cells (APC). Interaction of these B7 molecules with CD28 and CTLA-4 expressed on T cells is a critical step in T cell activation. Previously, we reported that Mycobacterium tuberculosis infection in the combined absence of B7.1 and B7.2 resulted in impaired host resistance to the pathogen. Despite their structural similarities, the individual contribution of B7.1 and B7.2 to the development of pathogenic T cells in autoimmune diseases and protective T cells in infectious diseases is markedly distinct. In the current study, we therefore examined whether B7.1 and B7.2 have discrete, equivalent, or overlapping functions in mediating host resistance to M. tuberculosis. We found that the individual absence of either B7.1 or B7.2 had no effect on the ability of the host to contain bacterial load in the lungs, recruit immune cells to the lung, generate a Th1 response, or induce a pulmonary granulomatous response. These results indicate that B7.1 and B7.2 molecules have equal ability to mediate host resistance to M. tuberculosis, underscoring the therapeutic utility of individual B7.1 and B7.2 antagonists in treating inflammatory disorders.


Subject(s)
B7-1 Antigen/metabolism , B7-2 Antigen/metabolism , Lymphocyte Activation/immunology , Mycobacterium tuberculosis/immunology , Tuberculosis/immunology , Animals , Antigen-Presenting Cells/metabolism , B7-1 Antigen/deficiency , B7-1 Antigen/genetics , B7-2 Antigen/deficiency , B7-2 Antigen/genetics , CD28 Antigens/immunology , CTLA-4 Antigen/immunology , Cells, Cultured , Cytokines/biosynthesis , Cytokines/immunology , Female , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Tuberculosis/prevention & control
5.
Arterioscler Thromb Vasc Biol ; 33(10): 2374-9, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23908246

ABSTRACT

OBJECTIVE: Abdominal aortic aneurysm is an inflammatory disease leading to destructive vascular remodeling and ultimately to lethal aortic rupture. Despite its frequent association with atherosclerosis, compelling studies have shown striking differences and potentially opposite roles of T-cell helper responses in aneurysm as compared with atherosclerosis, casting doubt on the relevance and suitability of T-cell-targeted therapies in this context. APPROACH AND RESULTS: Here, we show that selective depletion of T regulatory (Treg) cells using a CD25-specific monoclonal antibody significantly enhances the susceptibility of C57Bl/6 mice to angiotensin II-induced abdominal aortic aneurysm and promotes aortic rupture (n=25-44 mice/group). Similar results are observed in angiotensin II-treated Cd80(-/-)/Cd86(-/-) or Cd28(-/-) mice with impaired Treg cell homeostasis (n=18-23 mice/group). Treg cell depletion is associated with increased immune cell activation and a blunted interleukin (IL)-10 anti-inflammatory response, suggesting an immunoinflammatory imbalance. Interestingly, Il-10(-/-) mice (n=20 mice/group) show increased susceptibility to angiotensin II-induced abdominal aortic aneurysm and aortic rupture and are insensitive to Treg cell depletion. Finally, reconstitution of Cd28(-/-) Treg-deficient mice with Treg cells (n=22 mice/group) restores a balance in the immunoinflammatory response, rescues the animals from increased susceptibility to aneurysm, and prevents aortic dissection. CONCLUSIONS: These results identify a critical role for Treg cells and IL-10 in the control of aneurysm formation and its progression to rupture and suggest that therapies targeting Treg responses may be most suited to treat aneurysmal disease.


Subject(s)
Angiotensin II , Aorta, Abdominal/immunology , Aortic Aneurysm, Abdominal/prevention & control , Aortic Rupture/prevention & control , T-Lymphocytes, Regulatory/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Aorta, Abdominal/pathology , Aortic Aneurysm, Abdominal/chemically induced , Aortic Aneurysm, Abdominal/immunology , Aortic Aneurysm, Abdominal/pathology , Aortic Rupture/chemically induced , Aortic Rupture/immunology , Aortic Rupture/pathology , B7-1 Antigen/deficiency , B7-1 Antigen/genetics , B7-2 Antigen/deficiency , B7-2 Antigen/genetics , CD28 Antigens/deficiency , CD28 Antigens/genetics , Cells, Cultured , Coculture Techniques , Disease Models, Animal , Inflammation Mediators/metabolism , Interleukin-10/deficiency , Interleukin-10/genetics , Interleukin-2 Receptor alpha Subunit/immunology , Leukocyte Reduction Procedures , Lymphocyte Activation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , T-Lymphocytes, Regulatory/transplantation , Time Factors
6.
J Leukoc Biol ; 94(2): 367-76, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23744647

ABSTRACT

Although T cell activation has been classically described to require distinct, positive stimulation signals that include B7-1 (CD80) and B7-2 (CD86) costimulation, overriding suppression signals that avert immune-mediated host injury are equally important. How these opposing stimulation and suppression signals work together remains incompletely defined. Our recent studies demonstrate that CD8 Teff activation in response to cognate peptide stimulation is actively suppressed by the Foxp3(+) subset of CD4 cells, called Tregs. Here, we show that the elimination of Treg suppression does not bypass the requirement for positive B7-1/B7-2 costimulation. The expansion, IFN-γ cytokine production, cytolytic, and protective features of antigen-specific CD8 T cells stimulated with purified cognate peptide in Treg-ablated mice were each neutralized effectively by CTLA-4-Ig that blocks B7-1/B7-2. In turn, given the efficiency whereby CTLA-4-Ig overrides the effects of Treg ablation, the role of Foxp3(+) cell-intrinsic CTLA-4 in mitigating CD8 Teff activation was also investigated. With the use of mixed chimera mice that contain CTLA-4-deficient Tregs exclusively after the ablation of WT Foxp3(+) cells, a critical role for Treg CTLA-4 in suppressing the expansion, cytokine production, cytotoxicity, and protective features of peptide-stimulated CD8 T cells is revealed. Thus, the activation of protective CD8 T cells requires positive B7-1/B7-2 costimulation even when suppression by Tregs and in particular, Treg-intrinsic CTLA-4 is circumvented.


Subject(s)
B7-1 Antigen/antagonists & inhibitors , B7-2 Antigen/antagonists & inhibitors , CD8-Positive T-Lymphocytes/immunology , Lymphocyte Activation , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Abatacept , Adoptive Transfer , Animals , B7-1 Antigen/deficiency , B7-1 Antigen/physiology , B7-2 Antigen/deficiency , B7-2 Antigen/physiology , Cytotoxicity, Immunologic , Forkhead Transcription Factors/analysis , Immunoconjugates/pharmacology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Ovalbumin/immunology , Peptide Fragments/immunology , Radiation Chimera
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