Institute of Biomedical Studies

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Browsing Institute of Biomedical Studies by Author "Banchereau, Jacques."

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    Gene expression profiling to understand the alterations in the monocyte compartment of pediatric systemic lupus erythematosus.
    (2008-06-11T17:41:33Z) Patel, Pinakeen Shankarbhai.; Pascual, Virginia.; Banchereau, Jacques.; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.
    Blood monocytes from SLE patients display DC function, as they are able to induce the proliferation of allogeneic T cells. Furthermore, sera from SLE patients induce healthy monocytes to differentiate into DCs. This DC-inducing property is in part due to the presence of type-I IFNs in SLE sera, as well as other, yet uncharacterized factors. To understand these alterations, we performed a thorough phenotypic analysis and gene expression profiling of monocytes from children with active, newly diagnosed and untreated disease. Phenotypic analysis of freshly isolated SLE blood monocytes revealed a modest expansion of CD14highCD16+ cells and an otherwise lack of expression of molecules related to DC function. Further characterization of a fraction of SLE monocytes inducing allogeneic T cell proliferation revealed that upon contact with T cells, SLE monocytes secrete proinflammatory cytokines such as IL-1 and IL-6 and do upregulate expression of innate immunity receptors involved in DC differentiation and molecules responsible for antigen presentation. To recapitulate the initial events leading to monocyte differentiation in this disease, we studied the effects of SLE serum on healthy monocyte at the trasncriptional and protein levels. These studies revealed the upregulation of expression on these cells of chemokine receptor such as CX3CR1 and CCR7, which may lead to the migration of blood monocytes to inflammed tissues and/or secondary lymphoid organs respectively in vivo. There, contact with T cells would lead to the acquisition of antigen presenting function and skewing from tolerogenic to immunogenic responses.
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    Humanized mice to test vaccination against influenza virus via dendritic cells.
    (2008-06-11T14:19:03Z) Yu, Chun-I, 1975-; Palucka, Karolina.; Banchereau, Jacques.; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.
    Critical to the development of human vaccines is the availability of in vivo models of the human immune system that permit testing of vaccine efficacy. Here,we used NOD-SCID-β²m-/- immunodeficient mice which, when engrafted with human CD34⁺ hematopoietic progenitors, develop all subsets of human dendritic cells(DCs) and B cells. T cells and their subsets were reconstituted by adoptive transfer. We found myeloid DCs, plasmacytoid DCs and monocytes in the bone marrow, spleen, and peripheral tissues including skin and lungs. To test DC biologyin vivo, we first used live influenza A/PR8/34 (H1N1) virus. Upon intranasal inoculation, all subsets of human antigen presenting cells were activated. Matured DCs were found accumulated in mediastinal lymph nodes. To evaluate the value of these mice for testing human vaccines, humanized mice were immunized with1) ex vivo-generated DCs, 2) seasonal influenza vaccines and 3) protein antigens fused to anti-DC receptor. Upon vaccination with ex vivo-generated DCs pulsed with heat-inactivated influenza virus, mice developed influenza-specific immunity, i.e. influenza-specific immunoglobulins (Igs) in the serum and influenza virus matrix protein 1 (FluM1)-specific CD8⁺ T cells in the blood, spleen and lungs. Influenza-specific Igs were protective as sera from vaccinated mice inhibited influenza virus-induced hemagglutination in vitro and offered passive protection in vivo. Upon vaccination with seasonal influenza vaccines, i.e. live attenuated trivalent vaccine (LAIV) or killed trivalent vaccine (TIV), humanized mice developed both humoral and cellular immunity. Plasma cells differentiation and the secretion of specific Igs were dependent on the reconstitution with CD45RA⁻CD27⁺CD4⁺ central memory T cells. CD8⁺ T cells specific to two influenza antigens, i.e. FluM1 and NS1, were detected in mice vaccinated with LAIV. TIV-vaccinated mice showed the expansion of FluM1, but not NS1, specific CD8⁺ T cells. Antigen-specific CD8⁺ T cells produced IFN-γ and expressed surface CD107a consistent with the acquisition of effector function. Finally, upon vaccination with anti-DC receptor (DCIR)-FluM1 fusion protein and poly I:C as an adjuvant, DCs efficiently cross-presented FluM1 and expanded antigen-specific CD8⁺T cells. Therefore, humanized mice might be valuable model for testing human vaccines against influenza virus.
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    The chromatin accessibility signature of aging in human blood leukocytes stem from CD8+ T cells.
    (2017-07-26) Chung, Cheng-Han, 1982-; Banchereau, Jacques.
    Human aging is linked to changes in immune function that contribute to decreased responses to pathogens and increased systemic inflammation. Human aging is also associated with profound epigenetic changes across cell types and tissues. How these changes affect the aging –associated decline of the immune system is unknown. The Assay for Transposase Accessible Chromatin with sequencing technology (ATAC-seq) allowed us to study, at a system biology level, the open chromatin landscapes of human peripheral blood mononuclear cells (PBMCs), monocytes, purified B and T cell subsets from healthy young and healthy elderly individuals. We captured aging-associated epigenomic remodeling in PBMCs consisting of (1) systematic chromatin closing at promoters and enhancers targeting the T cell signaling and development and (2) chromatin opening, mostly at quiescent and repressed sites associated with cytotoxicity. Transcriptome profiling of the same individuals revealed gene expression changes concordant with epigenomic changes. Analysis of naïve and memory CD4+ and CD8+ T cell subsets demonstrated that the epigenomic signature of aging in PBMCs arises mostly from memory CD8+ T cells, indicating that aging differentially affects T cell epigenomes in a subset-specific manner. This study provides the first systems-level description of chromatin accessibility changes associated with immune aging in human PBMCs and T cell subsets. It revealed in PBMCs significant chromatin closing at promoters and enhancers, including at the IL7R locus and the IL-7 signaling pathway. Our study revealed individual-level variability in aging-associated chromatin remodeling and provided a systematic and modular tool for assessing deviations from chronological age. The open chromatin profiling of sorted T cell subsets, concluded that the chromatin “aging signature” captured in PBMCs, mostly stems from memory CD8+ T cells. The combined ATAC-seq/RNA-seq analyses uncovered epigenetic changes poised for expression changes and active noncoding elements (e.g., enhancers), both of which will be essential for understanding the regulatory mechanisms underlying immunosenescence. Nevertheless, ATAC-seq based open chromatin profiling is a straightforward approach to identify functional genomic regulatory regions, master regulators, and gene regulatory networks controlling complex in vivo processes. In our lab, ATAC-seq is utilized to understand the epigenetics differences in different immune cells and diseases.