HIV-1 Infection Results in Sphingosine-1-Phosphate Receptor 1 Dysregulation in the Human Thymus.

Regeneration of functional naïve T lymphocytes following the onset of human immunodeficiency virus (HIV) infection remains a crucial issue for people living with HIV (PLWH), even when adhering to antiretroviral therapy (ART). Thus far, reports on the impact of HIV-1 infection on the entry of thymic precursors and the egress of functional naïve T lymphocytes to and from the thymus are limited. We examined the impact of HIV-1 on Sphingosine-1-phosphate (S1P) signaling, which governs the egress of functional naïve thymocytes from the thymus to the periphery.

Characterization of T Follicular Helper Cells and T Follicular Regulatory Cells in HIV-Infected and Sero-Negative Individuals.

Humoral immune response is important in fighting pathogens by the production of specific antibodies by B cells. In germinal centers, T follicular helper (TFH) cells provide important help to B-cell antibody production but also contribute to HIV persistence. T follicular regulatory (TFR) cells, which inhibit the function of TFH cells, express similar surface markers.

A Novel HIV-1 Nef Mutation in a Primary Pediatric Isolate Impairs MHC-Class I Downregulation and Cytopathicity.

HIV-1-induced cytopathicity of thymocytes is a major cause of reduced peripheral T cells and rapid disease progression observed in HIV-1-infected infants. Understanding the virulence factors responsible for thymocyte depletion has paramount importance in addressing the pathogenesis of disease progression in children. In this study, thymocyte depletion was analyzed following infection with two primary CXCR4-tropic HIV-1 pediatric isolates (PI), PI-2 and PI-2.

Histoarchitectural Deterioration of Lymphoid Tissues in HIV-1 Infection and in Aging.

Impaired immunity is a common symptom of aging and advanced Human Immunodeficiency Virus type 1 (HIV-1) disease. In both diseases, a decline in lymphocytic function and cellularity leads to ineffective adaptive immune responses to opportunistic infections and vaccinations. Furthermore, despite sustained myeloid cellularity there is a background of chronic immune activation and a decrease in innate immune function in aging.

TGF-β Sustains Tumor Progression through Biochemical and Mechanical Signal Transduction.

Transforming growth factor β (TGF-β) signaling transduces immunosuppressive biochemical and mechanical signals in the tumor microenvironment. In addition to canonical SMAD transcription factor signaling, TGF-β can promote tumor growth and survival by inhibiting proinflammatory signaling and extracellular matrix (ECM) remodeling. In this article, we review how TGF-β activated kinase 1 (TAK1) activation lies at the intersection of proinflammatory signaling by immune receptors and anti-inflammatory signaling by TGF-β receptors.

Urbanization and anticoagulant poisons promote immune dysfunction in bobcats.

Understanding how human activities influence immune response to environmental stressors can support biodiversity conservation across increasingly urbanizing landscapes. We studied a bobcat () population in urban southern California that experienced a rapid population decline from 2002-2005 due to notoedric mange. Because anticoagulant rodenticide (AR) exposure was an underlying complication in mange deaths, we aimed to understand sublethal contributions of urbanization and ARs on 65 biochemical markers of immune and organ function.

CD31, a Valuable Marker to Identify Early and Late Stages of T Cell Differentiation in the Human Thymus.

Although CD31 expression on human thymocytes has been reported, a detailed analysis of CD31 expression at various stages of T cell development in the human thymus is missing. In this study, we provide a global picture of the evolution of CD31 expression from the CD34 hematopoietic precursor to the CD45RA mature CD4 and CD8 single-positive (SP) T cells. Using nine-color flow cytometry, we show that CD31 is highly expressed on CD34 progenitors and stays high until the early double-positive stage (CD3CD4CD8αβ).

Sphingosine-1-phosphate/sphingosine-1-phosphate receptor 1 signaling is required for migration of naive human T cells from the thymus to the periphery.

Background: The mechanisms that govern the egress of mature thymocytes from the human thymus to the periphery remain understudied yet are of utmost importance to the field of basic immunology, as well as T-cell reconstitution in various immunodeficiencies. We examined the expression and function of sphingosine-1-phosphate (S1P) receptors in human thymocyte egress.

Objectives: We aimed to determine whether S1P receptors (S1P-Rs) play a role in mature human thymocyte egress and to identify the thymocyte population or populations that express S1P-Rs and respond to S1P by migrating across a concentration gradient.

Human T-Cell Development and Thymic Egress: An Infectious Disease Perspective.

Emigration of mature naïve CD4 SP T cells from the human thymus to the periphery is not fully understood, although elucidation of the mechanisms that govern egress of T cells is crucial to understanding both basic immunology and the immune response in diseases such as HIV infection. Recent work has brought to light the requirement for sphingosine-1-phosphate (S1P) and its receptors in a variety of fields including mature naïve T-cell egress from the thymus of mice. We are examining the expression and function of this novel requisite T-cell egress receptor within the human thymus, characterizing changes observed in the expression and function of this receptor in infectious diseases.

The plasmacytoid dendritic cell as the Swiss army knife of the immune system: molecular regulation of its multifaceted functions.

Plasmacytoid dendritic cells (pDC) have been regarded as the "professional type I IFN-producing cells" of the immune system following viral recognition that relies on the expression of TLR7 and TLR9. Furthermore, pDC link the innate and adaptive immune systems via cytokine production and Ag presentation. More recently, their ability to induce tolerance and cytotoxicity has been added to their "immune skills.

BST2/Tetherin is constitutively expressed on human thymocytes with the phenotype and function of Treg cells.

In contrast to peripheral plasmacytoid DCs (pDCs), thymic pDCs constitutively express low levels of IFN-α. This leads to induction of interferon secondary genes (ISGs) in medullary thymocytes, raising the question whether IFN-α may play a role in T-cell development. When characterizing further differences between peripheral and thymic pDCs, we found that thymic pDCs have a phenotype consistent with an "activated signature" including expression of TNF-α and bone marrow stromal cell antigen 2 (BST2), but no expression of ILT7.

MicroRNA-146a regulates survival and maturation of human plasmacytoid dendritic cells.

During microbial infections, plasmacytoid dendritic cells (pDCs) are a main source of type I interferons α/β (IFN-α/-β). Nucleic acids from microbes are sensed by Toll-like receptors 7/9 (TLR7/9), which are selectively expressed in pDCs. Activated pDCs also produce proinflammatory cytokines and upregulate costimulatory molecules.

HIV-1 infection of hematopoietic progenitor cells in vivo in humanized mice.

HIV infection has been associated with defective hematopoiesis since the earliest days of the HIV/AIDS epidemic. Generation of all hematopoietic lineages suffers in the face of infection. The mechanisms by which HIV impairs normal blood cell development remain unclear, and direct infection of intermediate hematopoietic progenitors has not been established as a source of HIV-associated hematopoietic pathology.

IL-21-stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs their capacity to induce T-cell proliferation.

Plasmacytoid dendritic cells (pDCs) play a crucial role during innate immunity by secreting bulk amounts of type I interferons (IFNs) in response to Toll-like receptor (TLR)-mediated pathogen recognition. In addition, pDCs can also contribute to adaptive immunity by activation of antigen-specific T cells. Furthermore, it is well established that pDCs contribute to the pathogenesis of autoimmune diseases, including lupus.

GLI2 regulates TGF-β1 in human CD4+ T cells: implications in cancer and HIV pathogenesis.

Elevated levels of the immunoregulatory cytokine TGF-β1 in cancer and HIV infection have been linked to the suppression of protective immune responses. The transcriptional regulation of TGF-β1 is complex and still not completely understood. We report here for the first time that the transcription factor GLI2 regulates the expression of TGF-β1 in human CD4(+) T cells.

A doxycycline-dependent human immunodeficiency virus type 1 replicates in vivo without inducing CD4+ T-cell depletion.

A novel genetic approach for the control of virus replication was used for the design of a conditionally replicating human immunodeficiency virus (HIV) variant, HIV-rtTA. HIV-rtTA gene expression and virus replication are strictly dependent on the presence of a non-toxic effector molecule, doxycycline (dox), and thus can be turned on and off at will in a graded and reversible manner. The in vivo replication capacity, pathogenicity and genetic stability of this HIV-rtTA variant were evaluated in a humanized mouse model of haematopoiesis that harbours lymphoid and myeloid components of the human immune system (HIS).

IFN-α is constitutively expressed in the human thymus, but not in peripheral lymphoid organs.

Type I interferons have been typically studied for their effects in the context of bacterial or viral infections. However in this report, we provide evidence that Interferon-alpha (IFN-α) expressing cells are present in the thymus in the absence of infection. We show that pDC express the highest level of IFN-α and that MxA, which is exclusively expressed after engagement of the type I IFN receptor by IFN-α/β, is expressed in normal fetal and post-natal thymus, but not in the periphery.

Immune dysregulation after cardiothoracic surgery and incidental thymectomy: maintenance of regulatory T cells despite impaired thymopoiesis.

Thymectomy is performed in infants during cardiothoracic surgery leaving many patients with reduced thympopoiesis. An association between immune disorders and regulatory T cells (Treg) after incidental thymectomy has not been investigated. Questionnaires soliciting symptoms of atopic or autoimmune disease and biomarkers were measured in children and adults with congenital heart disease and either reduced or preserved thymopoiesis.

Correlation of immune activation during late pregnancy and early postpartum with increases in plasma HIV RNA, CD4/CD8 T cells, and serum activation markers.

A previously observed rise in the plasma viral load postpartum in both treated and untreated HIV-positive women remains unexplained. Virological and immunological markers were evaluated in HIV-negative controls and HIV-positive pregnant women with and without antiretroviral treatment. Plasma HIV RNA, CD4/CD8 T cells, and serum activation markers were sequentially measured during the third trimester, at delivery, and 2 to 8 weeks postpartum in a cohort of HIV-positive pregnant women (n = 96) enrolled in a maternal-fetal HIV transmission study and a control group of HIV-negative pregnant women (n = 28).

Signaling through the P38 and ERK pathways: a common link between HIV replication and the immune response.

One of the defining characteristics of HIV is its ability to manipulate the human immune response to promote its own replication. Since the beginning of the epidemic, there has been controversy whether a robust immune response to the virus is beneficial or detrimental for the host. Therefore, the effects of HIV on signaling pathways and cytokine production need to be characterized in order to distinguish between protective immune responses and inappropriate immune activation.

Isolation and in vitro generation of gene-manipulated human plasmacytoid and conventional dendritic cells.

Our understanding of human lymphocyte development has increased significantly over the past 20 years. In particular, our insight into human T- and B-cell development has improved (1, 2). Nonetheless, there are many gaps in our understanding, particularly regarding the early stages of development of hematopoietic progenitor cells (HPCs) into downstream lineage-biased and lineage-restricted precursors and the molecular mechanisms underlying these activities.

Persistent gammaherpesvirus replication and dynamic interaction with the host in vivo.

Gammaherpesviruses establish life-long persistency inside the host and cause various diseases during their persistent infection. However, the systemic interaction between the virus and host in vivo has not been studied in individual hosts continuously, although such information can be crucial to control the persistent infection of the gammaherpesviruses. For the noninvasive and continuous monitoring of the interaction between gammaherpesvirus and the host, a recombinant murine gammaherpesvirus 68 (MHV-68, a gammaherpesvirus 68) was constructed to express a firefly luciferase gene driven by the viral M3 promoter (M3FL).

Spi-B inhibits human plasma cell differentiation by repressing BLIMP1 and XBP-1 expression.

The terminal differentiation of B cells into antibody-secreting plasma cells is tightly regulated by a complex network of transcription factors. Here we evaluated the role of the Ets factor Spi-B during terminal differentiation of human B cells. All mature tonsil and peripheral blood B-cell subsets expressed Spi-B, with the exception of plasma cells.